She also had supporting roles in the films Pulse (2006), My Best Friend's Girl (2008), The Last House on the Left and in Powder Blue (2009), Much Ado About Nothing (2012), Fun Size (2012), The Lego Batman Movie (2017), Under the Silver Lake (2018), Knives Out (2019), King Tweety (2020), and Afraid (2024).

[6] Her subject was United States Representative Carolyn McCarthy (D-NY), whose outrage at the murder of her husband during the 1993 Long Island Rail Road shooting compelled her to challenge and win the seat held by her congressman, who had voted to repeal the Federal Assault Weapons Ban.

[10][11] She guest-starred on the television series The Big Bang Theory as Ramona Nowitzki, a controlling graduate student obsessed with Sheldon Cooper, in seasons two, ten and eleven (2008, 2017).

[15] From 2010 to 2013, she developed and hosted the Nerdist podcast Making It with Riki Lindhome, interviewing people in the entertainment industry about their rise to fame.

[18] She played a female version of Conrade, one of Don John's followers with whom he has a steamy relationship in Joss Whedon's Much Ado About Nothing, and appeared as the "Galaxy Scout" costume-wearing Denise in the 2012 comedy film Fun Size.

[19][20] In 2013, she starred in the horror-comedy film Hell Baby as Marjorie, the protagonist's Wiccan sister, a role for which she did a full frontal nude scene that attracted attention for being unusually lengthy.

The show, which focuses on the Bellacourts, a fictional aristocratic family living in Newport, Rhode Island at the turn of the 20th century, premiered in June 2015.

[32][33] In October 2020, she starred in the comedy thriller film The Wolf of Snow Hollow, directed by Jim Cummings, as sympathetic yet professional local police officer Julia Robson.

[39] As of November 2021[update], Lindhome will write the script for the upcoming animated musical film Steps; she will also executive-produce, and will co-write the lyrics with Micucci.