She began her career playing Rebecca Tyree on the ABC daytime television soap opera All My Children (1999–2001) before going on to star in the Lifetime crime drama series, Angela's Eyes (2006).

Spencer has appeared in many films, including In My Sleep (2010), Cowboys & Aliens (2011), This Means War (2012), Chasing Mavericks (2012), The Haunting in Connecticut 2: Ghosts of Georgia (2013), Oz the Great and Powerful (2013), and This Is Where I Leave You (2014).

[3] In the following years, she began playing guest roles on several television series, including CSI: Crime Scene Investigation, How I Met Your Mother, Private Practice and Castle.

Spencer played the role of a blogging enthusiast in Twix advertisements, and portrayed Miss Farrell, a love interest of Don Draper, on AMC's Mad Men in 2009.

[10][11] Spencer has appeared in several films, including In My Sleep (2010), Cowboys & Aliens (2011), This Means War (2012), and Chasing Mavericks (2012), and she played the lead role in The Haunting in Connecticut 2: Ghosts of Georgia (2013).

[16][17][18] Spencer played the lead role in the indie drama A Beautiful Now, written by Daniela Amavia, about a passionate dancer who finds herself considering an extreme act when she reaches a crossroads in her life.

[23][24] In 2016, Spencer was cast as lead character Lucy Preston in the NBC series Timeless,[25] where she plays a history professor sent on time travel missions to different eras in an effort to prevent others from disrupting the U.S.-related timestream.