The 44-year-old actor and 45-year-old actress announced the news in a joint statement to People magazine Monday.
"With great sadness, we have decided to separate, after 18 years of love and shared history," the pair said. "We will continue to be supportive of each other in every possible way moving forward."
Hamm and Westfeldt were last seen together at the Wet Hot American Summer: First Day of Camp premiere after-party July 22, where Page Six reported the couple were "canoodling" and looked "very much together." The pair had denied split rumors in April following Hamm's rehab stint.
The actor and actress collaborated on several movies, including the 2001 romantic comedy Kissing Jessica Stein. Hamm, best known for the AMC series Mad Men, is scheduled for High Wire Act with Rosamund Pike and Keeping Up with the Joneses with Isla Fisher.