[6] In the early 80s, his father grew frustrated with Margaret Thatcher's administration and moved his family to Tampa, Florida, United States when Mandvi was 16.

[11] Mandvi played Melchior in On the Razzle by Tom Stoppard at the Williamstown Theatre Festival and appeared in the docudrama Guantanamo: Honor Bound to Defend Freedom at the Culture Project.

He played the lead role of Amir, a Pakistani- American lawyer struggling with his identity and Islam in the drama by Ayad Akhtar.

[14] In October 2013, during a segment on The Daily Show, Mandvi interviewed Don Yelton of the North Carolina Republican Party office.

He had a major supporting role in the independent film American Chai, playing the lead character's roommate, "Engineering Sam."

He played the doctor who diagnosed Paul Vitti's (Robert De Niro) panic attacks in Analyze This, and had a role as Mr. Aziz of "Joe's Pizza" in Spider-Man 2.

Mandvi played a dentist alongside Ricky Gervais in the 2008 romantic comedy Ghost Town, as well as office employee Bob Spaulding in The Proposal, starring Sandra Bullock.

[20] He appeared in It's Kind of a Funny Story, a coming-of-age film written and directed by Anna Boden with Ryan Fleck, adapted from the 2006 novel by Ned Vizzini.

Mandvi played the role of Mr. Chetty in the 2013 comedy The Internship and portrayed Ash Vasudevan in the 2014 film Million Dollar Arm.

On 27 August 2017, Mandvi married his girlfriend of three years, Shaifali Puri, an author and humanitarian, at The Fox Theatre in Atlanta, GA.[23][24] They have one son, born 14 March 2020.

[26] In June 2019, he was awarded an Honorary Doctor of Humane Letters Degree by the Macaulay Honors College after delivering the commencement speech that year.