Lindhome was born on March 5, 1979 in Coudersport, Pennsylvania, and grew up in Portville, New York. She is primarily of Swedish ancestry. She studied at Syracuse University and was part of the Sketch comedy group known as Syracuse Live. After graduating in 2000, she embarked on an acting career.
After graduating from university, despite not having an agent, Lindhome was able to land a small role on the sitcom Titus and a minor role in the season seven episode "Him" of the popular television series Buffy the Vampire Slayer. In 2003, Lindhome got her first big break, earning a spot in Tim Robbins' Actor's Gang theater group and appearing in the play Embedded. She was one of four actors from the play to then be cast in the Academy Award-winning film Million Dollar Baby, where she played Mardell Fitzgerald, the sister of the main character.
In 2005, Lindhome had a recurring role on Gilmore Girls as Juliet, a friend and classmate of Logan Huntzberger and then Rory. In 2006, she wrote, produced, and co-directed the award-winning short film Life is Short, starring herself, Alexis Bledel, Samm Levine, and Seth MacFarlane. She also appeared in the 2006 film Pulse and in 2007 was one of many public figures to appear in the music video for Nickelback's "Rockstar".
During the 2007 writer's strike, Lindhome pursued more writing and directing opportunities. She performs as "Garfunkel" in the comedy-folk duo Garfunkel and Oates, with her friend and fellow Songwriter Kate Micucci. In 2011, she co-wrote a video with Glee cast member Heather Morris for Funny or Die called Nuthin' But a Glee Thang, a parody of the Dr. Dre song "Nuthin' but a 'G' Thang". She also hosts a Nerdist Industries podcast called "Making It".
In 2008, Lindhome had a minor role in the film Changeling, playing an examination nurse. She continued to guest star on several popular television series including The Big Bang Theory, Criminal Minds, and Pushing Daisies. In 2009, she starred in the feature film remake of the Wes Craven classic The Last House on the Left.
In 2012, Lindhome turned her hand to Shakespeare, appearing as a villain in Joss Whedon's adaptation of Much Ado About Nothing.
In 2015, Lindhome and Natasha Leggero created the Comedy Central series Another Period, which they also star in together. She also played the girlfriend of Fozzie Bear on the series The Muppets.
In 2017, Lindhome had a supporting role in The Lego Batman Movie, voicing supervillain Poison Ivy and The Wicked Witch of the West, though she did not receive billing for the latter role.
