Vance was born in San Diego County, California, to Telugu Indian immigrant parents and raised in an upper-middle-class suburb.

In 2019, Vance was admitted to the District of Columbia Bar, and she subsequently worked for a leading law firm handling civil litigation and appeals in cases involving higher education, local government, entertainment, and technology.

[20] She attended Yale University, graduating summa cum laude in 2007 with a bachelor's degree in history, with membership in Phi Beta Kappa.

[21] After graduating, she taught English and American history as a Yale–China Teaching Fellow at Sun Yat-sen University in Guangzhou, China.

[11][12][13] Her paternal ancestry can be traced to Chilukuri Buchipapayya Sastri (c. 18th century), who lived in Saipuram in Vuyyuru Mandal of Krishna district.

[33] Usha's paternal grandfather, Chilukuri Rama Sastri, taught physics at IIT Madras, and the institute now runs a student award in his memory.

[34] Her great-aunt Chilukuri Santhamma resides in Visakhapatnam, Andhra Pradesh, teaches physics at a private university, and has written an English interpretation of the Bhagavad Gita, a Hindu sacred text.

[41] Vance worked for the law firm Munger, Tolles & Olson for its San Francisco and Washington, D.C. offices as an associate for almost six years, handling civil litigation and appeals in cases involving higher education, local government, entertainment and technology, until July 2024, when she resigned "to focus on caring for our family".

[45][46][47] Vance previously worked as a summer associate at Williams & Connolly, Taft Stettinius & Hollister, and Levine Sullivan Koch & Schulz.

[65][66] In the same month, President Trump appointed Vance to serve as a member of the board of trustees of John F. Kennedy Center for the Performing Arts.

[67] While at Yale Law School, Usha Chilukuri met her future husband, JD Vance, a relationship encouraged by their professor Amy Chua.

[69] In 2013, Chilukuri and Vance collaborated to organize a discussion group at Yale focused on "social decline in white America".

[69][70] Chilukuri and Vance married in 2014 in Kentucky, in an interfaith marriage ceremony,[71][20] her husband's friend Jamil Jivani read from the Bible[72] and a Hindu pandit blessed the couple.

[84][85][86][87] Due to her Indian heritage, Vance has faced racist comments from white supremacists, including prominent far-right figures such as Nick Fuentes and Jaden McNeil.