Powell was born in Albany, Georgia. He lived in various places growing up, then graduated high school from Lindhurst High School in Linda, California. He then worked in a number of jobs before eventually settling in Santa Rosa, California, where he attended Sonoma State University. He earned a bachelor's degree in 1991 and a master's in 1993. Not long after completing his graduate work at Sonoma State, he entered the Iowa Writer's Workshop at the University of Iowa. In 1996, he graduated from Iowa and began a career as a poet and university professor. Powell has taught at a number of different universities, including Columbia University, Sonoma State University, San Francisco State University, and Harvard University, where he served as the Briggs-Copeland Lecturer in Poetry. In 2004, Powell left Harvard for The University of San Francisco, where he teaches in the English department.

In addition to serving as the Briggs-Copeland Lecturer at Harvard (itself a recognition of both creative and scholarly talent), Powell has won the Lyric Poetry Award from the Poetry Society of America, a grant for the National Endowment for the Arts, and a Paul Engle Fellowship. His second collection, Lunch, was a finalist for the National Poetry Series, and his third book, Cocktails, was a finalist for the National Book Critics Circle Award for Poetry.

On February 3, 2010, after the publication of Chronic in 2009, Claremont Graduate University announced that Powell had won its prestigious Kingsley Tufts Poetry Award.

Chronic also won the 2009 Northern California Book Award and the 2009 California Book Award.

Considered by some an experimental poet, Powell mixes both conventional and non-conventional techniques. For example, his early poems do not have titles; the first lines serve as the poem's working title. He also does not capitalize the first letter of a new sentence. In this sense, he is reminiscent of E. E. Cummings; however Powell's poems are more edgy. His work often moves back and forth between popular culture like movies and music and more complicated themes like religion and AIDS; he uses numerous rhetorical devices, especially puns, as bridges between these two spheres of experience. Powell's first three books of poems are considered a kind of trilogy on the AIDS epidemic.

Writing in the New York Times, critic Stephen Burt said of Powell's work, "No accessible poet of his generation is half as original, and no poet as original is this accessible."

Powell's publications include Tea (Wesleyan, 1998); Lunch (Wesleyan, 2000); and Cocktails (Graywolf Press, 2004). Powell's fourth collection, Chronic was published by Graywolf in February 2009, receiving numerous accolades, including the Kingsley Tufts Poetry Award and the California Book Award. Both Cocktails and Chronic were finalists for the Thom Gunn Poetry Award and the National Book Critics Circle Award in Poetry.

Powell and American poet David Trinidad co-authored By Myself: An Autobiography (Turtle Point Press, 2009), the experimental memoir of a manufactured celebrity who refers only to him/herself as "myself."

A bilingual selection from Powell's four collections has been published in Germany Cocktails (luxbooks, 2009).