Plouffe was raised in Wilmington, Delaware and attended St. Mark's High School. He left the University of Delaware in 1989 to pursue a full time career in politics, and completed his full undergraduate degree in May 2010.

Plouffe began his political career when he went to work for Senator Tom Harkin's 1990 re-election campaign. He later worked as a state field director for Harkin's unsuccessful 1992 Presidential campaign. In the same year he successfully managed Congressman John Olver's first re-election bid in Massachusetts. In 1994 Plouffe managed Delaware Attorney General Charles M. Oberly's unsuccessful campaign against Senator William V. Roth. He then worked as campaign director for the Democratic Senatorial Campaign Committee in 1995. In 1996 Plouffe managed Bob Torricelli's successful campaign to fill Bill Bradley's New Jersey seat in the United States Senate.

From 1997 to 1998 Plouffe served as Democratic leader Dick Gephardt's Deputy Chief of Staff. In 1999-2000, as executive director of the Democratic Congressional Campaign Committee, Plouffe led Democrats to gains that came within several thousand votes of winning back the House.

In the winter of 2000, Plouffe joined AKP&D Message and Media but left briefly to serve as a strategist for Gephardt's unsuccessful Presidential bid. He returned to the firm and became a partner in February 2004. Beginning in 2003, Plouffe and fellow AKP&D partner David Axelrod worked on Barack Obama's 2004 Illinois Senate campaign, beginning his association with Obama. Plouffe worked with Axelrod on the successful 2006 campaign of Deval Patrick for Governor of Massachusetts.

Plouffe was the campaign manager for Obama's successful 2008 presidential campaign. He is credited with the campaign's successful overall strategy in the race (primarily against Senator Hillary Clinton) for the Democratic Party presidential nomination, to focus on the first caucus in Iowa and on maximizing the number of pledged delegates, as opposed to focusing on states with primaries and the overall popular vote. He is also credited by The New Republic for Obama's success in the Iowa caucus and for crafting an overall strategy to prolong the primary past Super Tuesday. The Chicago Tribune writes, "Plouffe was the mastermind behind a winning strategy that looked well past Super Tuesday's contests on Feb. 5 and placed value on large and small states." Plouffe also maintained discipline over communications in the campaign, including controlling leaks and releasing information about the campaign on its terms. Averse to publicity himself, Plouffe's control over the internal workings of the Obama campaign successfully avoided the publicly aired squabbles that frequently trouble other campaigns.

In May, 2008, David Axelrod praised Plouffe, stating he had "done the most magnificent job of managing a campaign that I've seen in my life of watching presidential politics. To start something like this from scratch and build what we have built was a truly remarkable thing." After winning the election on November 4, Obama credited Plouffe in his acceptance speech, calling him "the unsung hero of this campaign, who built the . . . best political campaign, I think, in the history of the United States of America."

Plouffe is currently working as an outside senior adviser to the Obama administration. His book The Audacity to Win: The Inside Story and Lessons of Barack Obama's Historic Victory, discussing management strategies that he used in the 2008 campaign, was published on November 3, 2009. He later issued a video challenge for Obama supporters to buy a copy of his book on December 8, 2009 in order to "Beat Sarah Palin" and her best-selling book for one day. He also signed with the Washington Speakers Bureau to give paid speeches and plans to engage in non-government consulting work." In May 2009, Plouffe delivered the Convocation address at Cornell University. In January 2010, President Obama asked Plouffe to “give some extra time” to focus on the 2010 midterm elections. Plouffe’s outside advisory role consists of “working internally on strategy with” current White House officials. Plouffe's primary job on behalf of the White House will be to help devise, coordinate and analyze strategies for the House, Senate and governor's races in November.

Plouffe is married to Olivia Morgan, a Senior Advisor to Maria Shriver’s A Woman’s Nation and a Member of the President’s Committee on the Arts and the Humanities, and formerly an advisor to California Governor Gray Davis. The couple resides in Washington, D.C. and have a son and a daughter, the latter born two days after the 2008 Presidential election.