His earliest work was for D. C. Thomson's science fiction comic Starblazer in the mid-1980s. He wrote his first script for 2000 AD in 1986 and wrote the political superhero series New Statesmen for Crisis in 1988.

Many of his series for 2000 AD were tied into the same continuity, under the umbrella of Indigo Prime. Indigo Prime was a multi-dimensional organisation that policed reality, recruiting recently dead people as its agents. The climax of the series was Killing Time, in which agents Winwood and Cord pursued a demon that had hitched a ride on a Victorian time machine, one of the legitimate passengers of which turned out to be Jack the Ripper.

Other series for 2000 AD include Revere, a post-apocalyptic occult story with artist Simon Harrison, which was reprinted in its entirety in the 2000 AD Extreme Edition title in February 2007, and Firekind (1993), an anthropological science fiction story involving alien cultures and dragons, illustrated by Paul Marshall. He has also written Rogue Trooper and Judge Dredd.

For DC Comics' Vertigo imprint, he has written a fill-in on Hellblazer, and an eight-part series called Scarab, which started out as a revamp of Doctor Fate.

John has also written a run of Vampirella for Harris Comics.

Examples of John Smith's cross-referencing of characters throughout his oeuvre include:

• Renegade Indigo Prime agents Fervent and Lobe originally appeared in Tyranny Rex. Although Indigo Prime had only appeared in the Future Shock "A Change of Scenery" at that point, Smith said he always had the Smithiverse in mind: "They were both part of the same tailor-made Universe. That was intended right from the start."
• Characters from Pussyfoot 5 originally appeared in Devlin Waugh.
• The character Mr Cheetl originally appeared in Firekind but reappeared in Tyranny Rex and in Pussyfoot 5.
• Two members of Indigo Prime, Dazzler and Creed, appear in Scarab #7, "by that time I was probably just so sick of the thing I thought - 'Fuck it. I’ll rip off my own story' — and stuck in ‘Indigo Prime’ as a lazy way out.".
• Winwood and Cord appear in the last few pages of Dead Eyes uploading Danny's soul into a cloned body after the human race in his place (Reality 377) are killed.

Comics

Comics work includes:

• Starblazer:
• "Head Hunter" (with Segura, Starblazer #163, 1985)
• "Timeslay" (with Enrique Alcatena, Starblazer #168, 1986)

• Tharg's Future Shocks (collected in The Best of Tharg's Future Shocks, 160 pages, November 2008, ISBN 1-905437-81-1):
• "Time Enough to Tell" (with Barry Kitson, in 2000 AD #473, 1986)
• "Video" (with Geoff Senior, in 2000 AD #478, 1986)
• "A Change of Scenery" (with Nik Williams, in 2000 AD #490, 1986)
• "No Exit" (with Simon Harrison, in 2000 AD #559, 1988)
• "One Man's Meat" (with Massimo Belardinelli, in 2000 AD #563, 1988)
• "The Osmotic Man" (with Horacio Lalia, in 2000 AD #605, 1988)
• "Opening Moves" (with Mick Austin, in 2000 AD #629, 1989)
• "Earthsong" (with Steve Parkhouse, in 2000 AD #1480, 2006)

• Tales of Terror: "Perfect Vision" (with, Carol Lay, Eclipse Comics, 1987)

• Tyranny Rex:
• "Tyranny Rex" (with Steve Dillon, in 2000 AD #566-558, 1988)
• "Under Foreign Skies" (with Steve Dillon, in 2000 AD #582-584, 1988)
• Untitled (with Steve Dillon, in 2000AD Sci-Fi Special 1988)
• "Soft Bodies" (with Will Simpson, in 2000 AD #595-604, 1988)
• "Systems of Romance" (with Dougie Braithwaite, in 2000AD Sci-Fi Special 1989)
• Untitled (with Steve Sampson, in 2000AD Winter Special 1989)
• "Shadowground" (illustrated text story, with Duncan Fegredo, in 2000AD Annual 1991, 1990)
• "Touched by the Hand of Brendan" (with Mark Buckingham, in 2000AD Sci-Fi Special 1991)
• "A Twist in the Tale" (with Paul Marshall, in 2000AD Sci-Fi Special 1993)
• "Bitter Fruit" (with Paul Marshall, in 2000AD Yearbook 1994, 1993)
• "Deus ex Machina Book I" (with Mark Buckingham (#852-855) and Paul Marshall (#856-859), in 2000 AD #852-859, 1993)
• "Deus ex Machina Book II" (with Paul Marshall (#873-878) and Richard Elson (#879-880), in 2000 AD #873-880, 1994)
• "The Comeback" (with Steve Yeowell, in 2000 AD #1395-1399, 2004)

• New Statesmen:
• "Halcyon Days" (with Jim Baikie, in Crisis, #1, 1988)
• "Perspectives" (with Jim Baikie, in Crisis, #2, 1988)
• "Behind the light" (with Jim Baikie, in Crisis, #3, 1988)
• "Shadowdancing" (with Jim Baikie, in Crisis, #4, 1988)
• "Downtime" (with Sean Phillips, in Crisis, #5, 1988)
• "Holding the fist" (with Sean Phillips, in Crisis, #6, 1988)
• "Where the railroad meets the sea" (with Duncan Fegredo, in Crisis #7, 1988)
• "Memories on Ice" (with Duncan Fegredo, in Crisis #8, 1988)
• "All doors lead to the Minotaur" (with Jim Baikie, in Crisis, #9, 1989)
• "Life during wartime" (with Jim Baikie, in Crisis, #10, 1989)
• "Riding the tiger" (with Jim Baikie, in Crisis, #11, 1989)
• "The power and the glory" (with Jim Baikie, in Crisis, #12, 1989)
• "White Death" (with Sean Phillips, in Crisis, #13-14, 1989)
• "Epilogue" (with Jim Baikie, in Crisis, #28, 1989)

• Rogue Trooper: "Cinnabar" (with pencils by Steve Dillon and inks by Kev Walker, in 2000 AD #624-630 & 633-635, 1989)
• Inside Moves (with Chris Weston, in 2000 AD #631, 1989)
• Order of the Beast (with Dave D'Antiquis, in 2000 AD #632, 1989)

• Fervent and Lobe:
• "Issigri Variations" (with Mike Hadley, in 2000 AD #642-649, 1989)
• "Holiday on Ice" (with Mike Hadley, in 2000 AD Winter Special 1990)

• Indigo Prime:
• "Indigo Prime" (with Chris Weston, in 2000 AD #678, 1989)
• "Winwood and Cord" (with Chris Weston, in 2000 AD #680-681, 1990)
• "Fegredo and Brecht" (with Chris Weston, in 2000 AD #682, 1990)
• "Requiem" (illustrated, with Chris Weston, in 2000AD Winter Special 1990)
• "Almaranda: Solstice" (with Mike Hadley, in 2000 AD #720-721, 1991)
• "Killing Time" (with Chris Weston, in 2000 AD #735-744, 1991)
• "The Loa in the Machine" (illustrated, with Mick Austin, in 2000AD Winter Special 1992)
• "Weird Vibes" (text only, 2000AD Yearbook 1993)

• Mega City-One: "Resyko" (with Sean Phillips, in Judge Dredd Annual 1991, 1990)
• Danzig's Inferno (with Sean Phillips, in 2000 AD #718-719, February 1991)

• Rogue Trooper (Friday):
• "Hollow Town" (with Simon Coleby, in 2000 AD Sci-Fi Special 1991, July 1991)
• "Enfleshings" (with Chris Weston, in 2000 AD Yearbook 1993, September 1992)
• "Shock Tactics" (with Chris Weston, in 2000 AD Sci-Fi Special 1993, June 1993)

• Revere (with Simon Harrison):
• "Book I" (in 2000 AD #744-749, August—September 1991)
• "Book II" (in 2000 AD #809-814, 1992)
• "Book III" (in 2000 AD #867-872, 1993—1994)

• Strange Cases: "Skin Games" (with John Hicklenton, in Judge Dredd Megazine (vol. 1) #17, February 1992)
• Doctor Sin: "The Strange Case of the Wyndham Demon" (with John Burns, in 2000AD Action Special, March 1992)
• Hellblazer: "Counting To Ten" (with Sean Phillips, Hellblazer #51, Vertigo, March 1992)

• Tales from Beyond Science (with Rian Hughes):
• "The Eyes of Edwin Spendlove" (in 2000 AD #778, April 1992)
• "Secrets of the Organism" (in 2000 AD #779, April 1992)

• Devlin Waugh:
• Swimming in Blood (224 pages, 2004 ISBN 1-904265-17-0) collects:
• "Swimming in Blood" (with Sean Phillips, in Judge Dredd Megazine (vol. 2) #1-9, May 1992)
• "Brief Encounter" (with Sean Phillips, in Judge Dredd Megazine (vol. 2) #26, 1993)
• "A Love like Blood" (illustrated text story, with Sean Phillips, in Judge Dredd Mega-Special 1993, 1993)
• "Body and Soul" (illustrated text story, with Sean Phillips, in Judge Dredd Yearbook 1994, 1993)
• "Mouthful of Dust" (with Michael Gaydos, in Judge Dredd Megazine (vol. 3) #72-73, 2000)
• Red Tide (264 pages, 2005, DC ISBN 1-4012-0578-X, Rebellion ISBN 1-904265-29-4) collects:
• "Chasing Herod" (with Steve Yeowell, in 2000 AD #1149-1157, 1999)
• "Reign of Frogs" (with Steve Yeowell, in 2000 AD #1158-1167, 1999)
• "Sirius Rising" (with Steve Yeowell, in 2000 AD #1168-1173, 1999)
• "Red Tide Prologue" (with Colin MacNeil, in Judge Dredd Megazine #201, 2003)
• "Red Tide" (with Colin MacNeil, in Judge Dredd Megazine #202-213, 2003)
• "Vile Bodies" (with Colin MacNeil, in Judge Dredd Megazine #227, 2005)
• "All Hell" (with Colin MacNeil, in Judge Dredd Megazine #231-235 and 237, 2005)
• "Innocence & Experience" (with Peter Doherty, in Judge Dredd Megazine #253-256, 2007)

• Robo-Hunter: "Something for the Weekend, Sir?" (with Chris Weston, in 2000 AD Sci-Fi Special 1992, June 1992)
• Tales from Mega-City One: "Animal House" (with Chris Weston, in 2000AD Sci-Fi Special 1992, June 1992)

• Firekind (with Paul Marshall, in 2000 AD #828-840, 1993)
• Slaughterbowl (with Paul Peart, in 2000 AD #842-849, 1993)
• Scarab (with pencils by Scot Eaton and inks by Mike Barreiro, 8-issue limited series, Vertigo, 1993—1994)

• Judge Dredd:
• "The Jigsaw Murders" (with Xuasus, in Judge Dredd Megazine (vol. 2) #27-29, May 1993)
• "Ladonna Fever" (with David Millgate, in Judge Dredd Megazine (vol. 2) #30, June 1993)
• "Roadkill" (with Peter Doherty, in 2000 AD #856-858, October 1993)
• "Ballad of Cindy Crawlskin" (with Ashley Sanders, in Judge Dredd Megazine (vol. 3) #12, 1995)
• "Killing Grounds" (with Dean Ormston, in Judge Dredd Megazine (vol. 3) #13, 1996)
• "Mondo Simp" (with Paul Marshall, in Judge Dredd Megazine (vol. 3) #15-16, 1996)
• "Darkside" (with Paul Marshall, in 2000 AD #1017-1028, November 1996 - February 1997)
• "Fetish" (with Siku, in Judge Dredd Megazine (vol. 3) #26-30, 1997, collected in Devlin Waugh: Swimming in Blood)
• "Survivor Type" (with Simon Davis, in 2000 AD #1190, April 2000)
• "New Model Phoord" (with Paul Marshall, in 2000 AD #1197-1199, June 2000)
• "Meatmonger " (with Siku, in 2000 AD #1365-1370, November—December 2003)
• "Bite Fight!" (with John Burns, in Judge Dredd Megazine #224-225, 2004)
• "Jumped" (with Simon Fraser, in 2000 AD #1491-1494, 2006)
• "Old Wounds" (with Peter Doherty, in Judge Dredd Megazine #287-288, August—September 2009)

• "Red Shift" (with pencils by Rob Haynes, in Ultraforce #2, Malibu Comics, November 1995)

• Holocaust 12 (co-writer Chris Standley):
• "Skyfall" (with Jim Murray, in Judge Dredd Megazine (vol. 3) #20-23, 1996)
• "Storm Warning" (with Clint Langley, in Judge Dredd Megazine (vol. 3) #29-33, 1997)

• Vector 13: "Graven Images" (with Cliff Robinson, in 2000 AD #1064, 1997)
• Pulp Sci-Fi: "Feast of Skin" (with Chris Weston, in 2000 AD #1163, 1999)

• Pussyfoot 5:
• "Series One" (with Nigel Raynor, in 2000 AD #1184-1188, 2000)
• "Series Two" (with Steve Yeowell, in 2000 AD #1251-1256, 2001)

• A Love Like Blood (with Frazer Irving, in 2000 AD #1243-1249, 2001)
• Vampirella #4-12, 19-21 (Harris Comics, 2001—2003)
• "Triptych" (with pencils by David Finch, in X-Men Unlimited #35, Marvel Comics, July 2002)
• Leatherjack (with Paul Marshall, in 2000 AD #1450-1467, 2005, tpb, 128 pages, July 2007, ISBN 1-905437-31-5)

• Tales From the Black Museum:
• "Burn!" (with Adrian Salmon, in Judge Dredd Megazine #247, 2006)
• "Feeders and Eaters" (with Vince Locke, in Judge Dredd Megazine #250, 2006)

• Dead Eyes (with Lee Carter, in 2000 AD #1577-1588, 2008)
• Cradlegrave (with Edmund Bagwell, in 2000 AD #1633-1644, 2009)

Fiction

• "Passion" (in Red Stains, edited by Jack Hunter, 144 pages, Creation Books, 1992, ISBN 1871592089)