Keflezighi is first U.S. man to win Boston in 30 years
Keflezighi, who was born in Eritrea but is now a U.S. citizen, set an official time of two hours, eight minutes and 37 seconds.
Wilson Chebet of Kenya finished second and compatriot Frankline Chepkwony was third.
The last U.S. man to stand atop the podium on Boston's Boylston street was Greg Meyer, who won in 1983.
Kenya's Rita Jeptoo broke a 12-year course record as she successfully defended her women's Boston Marathon title on Monday.
Jeptoo pulled away from a pack of rivals that included U.S. runner Shalane Flanagan, who had led the women's group for the first 20 miles of the 26.2-mile race.
The previous women's record for the course was a time of 2:20:43 set in 2002 by Margaret Okayno of Kenya.
Jeptoo finished with an unofficial time of two hours, 18 minutes and 57 seconds. Buzunesh Deba of Ethiopia was second and compatriot Mare Dibaba third.