In May 2009, Harris was announced to have been cast in the Screen Gems Thriller film The Roommate. The film, also starring Leighton Meester and Cam Gigandet, centers on a college freshman whose roommate has a violent obsession with her. Harris portrays Irene Crew, a high-profile fashion designer. The film was shot on location at the University of Southern California in Los Angeles, and suffered numerous push-backs for unknown reasons. The film was eventually released in February 2011 to a $15.6 million opening weekend despite negative reviews from critics and went on to gross over $40 million worldwide.
In September 2009, Harris appeared in the sitcom television series pilot Friends with Benefits, which was picked up by NBC. It was originally set to air as a midseason replacement during the 2010–11 television season, but was delayed until August 2011. Harris took on the role of Sara Maxwell, a doctor desperate to find the right guy. The series premiered to a low 2.34 million viewers and to mixed reviews from critics. The rest of the season's inability to retain viewers guaranteed that the series was not renewed.
Harris became engaged to Supernatural actor Jensen Ackles in November 2009 and the couple married on May 15, 2010, in Dallas, Texas. It was announced on January 7, 2013, that the couple were expecting their first child together. Their daughter was born in May 2013. On August 10, 2016, the couple announced that they were expecting twins together, later in the year. Their twins, a son and a daughter, were born in December 2016.