Aside from his current role as Roger on AMC's series Mad Men, some of his more notable television roles have included union organizer Al Kahn on Homefront; Senator Walter Mondale in the HBO miniseries From the Earth to the Moon; guest appearances as Sam Truman, Will's brother, on Will & Grace; guest appearances as Michael Cassidy, Amy's estranged husband, on Judging Amy; guest appearances as Bill Kelley on Sex and the City; principal Dennis Martino on Ed; and college president Peter Benedict on Jack and Bobby. In March 2007, he began a series of appearances on Desperate Housewives portraying a suitor to Gabrielle Solis (Eva Longoria Parker).

Slattery played Paul Moore, boyfriend of Katherine Watson (portrayed by Julia Roberts) in the film Mona Lisa Smile. He portrayed "Howie" in David Lindsay-Abaire's Pulitzer Prize winning play, Rabbit Hole. He played Henry Cravely in Charlie Wilson's War.

Slattery also narrates Stephen King's latest novel Duma Key in the audio book production of the story.

Slattery graduated from The Catholic University of America in 1984. He is married to actress Talia Balsam. They have one child.