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.
Rita Jeptoo of Kenya won the women's elite race in 2:28:57, setting a course record in the process and defending her title.
Tatyana McFadden of the University of Illinois won the women's wheelchair race for the second straight year.
Amid tight security, some 36,000 athletes took part in the Boston Marathon in the first running of the race since last year's bombing.
Racers faced new security restrictions at the event, a reaction to the attack that killed three people and injured 264 when, authorities say, two ethnic Chechen brothers dropped homemade explosives in backpacks at the finish line.
This year’s race began with a moment of silence to commemorate the three people who died and the more than 260 who were injured when two pressure-cooker-type bombs were detonated near the finish-line area along Boylston Street, according to the Los Angeles Times.
Thousands of runners gathered at a park in downtown Boston before the race, preparing to board buses that would take them to the race's start line in Hopkinton, 26.2 miles west of Boston.
Track coach Robert Hollis, who had traveled from New Jersey for the race, admitted to some security worries.
"There is some nervousness. I wasn't scared until 15 minutes ago but when I saw all those cops and the dogs on the Amtrak train, I got a little nervous," he said. "We just live in a different age and time now."
Race organizers expanded the field by some 9,000 runners this year, to allow the roughly 5,000 athletes who had been left on the course last year when the twin pressure-cooker bombs went off near the finish line another chance to compete.
Amateur runners often work for years to post the strict age-graded times needed to qualify for the elite race.
Officials asked people not to bring backpacks--last year's bombs were hidden in backpacks--but insisted the race would be safe, the Los Angeles Times reported.
The bombs, located about 200 yards apart on Boylston Street, turned the finish line area to chaos. Dead were Krystle Campbell, 29; Lu Lingzi, 23; and Martin Richard, 8.Reuters and Los Angeles Times reported.