The series chronicles the political life of Selina Meyer, a former senator who becomes the Vice President of the United States. Initially enthusiastic about her role, Selina quickly finds that her position is largely powerless and filled with daily frustrations, miscommunications, and a team of misfit staff members who provide little support. Her ambitious Chief of Staff, Amy Brookheimer, often attempts to pull the strings behind the scenes, while her fiercely loyal personal aide, Gary Walsh, attends to her every whim. Selina’s aspirations for greater political influence are constantly thwarted by bureaucratic inertia, her relentless ambition clashing with the trivialities and ceremonious tasks she must perform. As she navigates the halls of power, she faces numerous obstacles from both rival politicians and her own gaffe-prone persona.

Through her often disastrous public appearances and strained relationships with colleagues and staff, Selina struggles to make a significant impact while managing her public image. The show explores the absurdities and chaos of U.S. politics, showcasing the backroom deals, gossip, and constant spin necessary to survive in the political limelight. Despite numerous setbacks and scandals threatening to upend her career, Selina remains relentlessly focused on climbing higher up the political ladder. The series offers a satirical look at the nature of politics and power, while portraying Selina's unwavering desire to leave a legacy amid the lunacy of Washington, D.C. politics.