Her performances as Virginia E. Johnson in the Showtime series Masters of Sex (2013–2016) and as Libby Epstein in FX on Hulu's Fleishman Is in Trouble have earned her nominations at the Primetime Emmy Awards.

Since then, she had series-regular roles in several television series including Related (2005–2006), Party Down (2009–2010; 2023), Das Boot (2018), Castle Rock (2019), Truth Be Told (2019), Fatal Attraction (2023), and Zero Day (2025).

Her other film appearances include My Best Friend's Girl (2008) Cloverfield (2008), Hot Tub Time Machine, 127 Hours (both 2010), Save the Date, Bachelorette (both 2012), The Interview (2014), Now You See Me 2, Allied (both 2016), and Cobweb (2023).

[17] Caplan began her acting career in 1999, first playing a girl named Sara in the critically acclaimed series Freaks and Geeks.

[citation needed] In 2005, Caplan played troubled sister Marjee Sorelli in Related, a one-hour comedy-drama on The WB that was canceled after one season.

[citation needed] She also appeared in the critically acclaimed Starz ensemble comedy Party Down, playing a struggling comedian who is part of a catering crew.

[citation needed] In 2013, she began playing 1960s human sexuality pioneer Virginia E. Johnson on the Showtime series Masters of Sex.

[24] Her performance on the show was well-reviewed, and on July 10, 2014, she was nominated for the Primetime Emmy Award for Outstanding Lead Actress in a Drama Series.

[25] Caplan was cast in her role as Johnson before they signed her co-star Michael Sheen as William H. Masters because he was busy working on another production.

[29] Maier stated that the developers of the show have remained mostly accurate to his book and have included other events that are historically relevant to St. Louis, where the series takes place and where Masters and Johnson lived.

[33] They had met in January 2015 while Caplan was filming Now You See Me 2[34] in London and made their red carpet debut as a couple at the Prague Opera Ball in February 2016.