The series follows the personal life and political career of Selina Meyer, the Vice President and later President of the United States. Her party affiliation is unknown, though hinted in the fourth season finale to be Democratic. Formerly a United States Senator from Maryland, Meyer campaigns for her party's nomination in the 2012 presidential election and is initially the front-runner, but ultimately loses the nomination to Stuart Hughes. Meyer subsequently joins the Hughes ticket as his running mate and is elected Vice President. Her staff as Vice President, upon whom Meyer is totally reliant, includes chief of staff Amy Brookheimer; director of communications Mike McClintock; deputy director of communications Dan Egan (Reid Scott); body man Gary Walsh; and personal secretary Sue Wilson. Later additions to her team as president include White House Chief of Staff Ben Cafferty and political strategist Kent Davison. Jonah Ryan, initially a White House liaison to the Vice President's office and later a New Hampshire congressman, also features prominently.
At the outset of the series, Meyer frequently finds herself relegated and ignored by Hughes. In the second season, Meyer comes to accrue some power and influence and, by the end of the season, is actively considering challenging Hughes for their party's nomination in the 2016 election. This becomes a moot point when Hughes decides not to seek a second term and Meyer begins her presidential campaign in the third season. Hughes abruptly resigns and Meyer assumes the presidency at the end of the season; the fourth season finds her adjusting to her new role while continuing her presidential campaign, both of which are undermined by a series of scandals. The election results in a tie between Meyer and challenger Bill O'Brien (Brad Leland), leading to a vote in the House of Representatives during the fifth season to decide the next president after a recount in Nevada fails to alter the election's outcome. The House vote ends in a tie, leading to the Senate voting to elect the Vice President. The Senate vote also ends in a tie; Meyer's Vice President Andrew Doyle, who did not run for a full term, casts the tiebreaking vote for O'Brien's running mate Laura Montez instead of Meyer's running mate Tom James, leading to Montez becoming president. The sixth season follows Meyer out of office for the first time in the series, as she attempts to ensure her legacy by authoring a memoir, setting up a foundation and attempting to establish a presidential library. At the end of the season, Meyer decides to run for president again.
The series also explores Meyer's personal life, such as her strained relationships with her daughter Catherine, ex-husband Andrew and a number of significant others. The lives, careers and relationships of the other characters are also explored, frequently intersecting with the series' principal narrative, satirizing the political activities and inner workings of the contemporary U.S. government.