"Here we have a relative newcomer," said Ethiopia's Gebregziabher Gebremariam, who finished third. "Everything changes."
In just his second race at the 26.2-mile distance, Desisa finished 5 seconds ahead of Kenya's Micah Kogo to earn $150,000 and the traditional olive wreath. American Jason Hartmann finished fourth for the second year in a row.
"It was more of a tactical race, the Ethiopian versus the Kenyans. That fight played out very well," defending champion Wesley Korir, a Kenyan citizen and U.S. resident, said after finishing fifth.
"The Ethiopians run very good tactical races. One thing I always say is, 'Whenever you see more than five Ethiopians in a race, you ought to be very careful.' As Kenyans, we ought to go back to the drawing board and see if we can get our teamwork back."
Rita Jeptoo won the women's race earlier for her second Boston victory. Jeptoo, who also won in 2006, finished in 2:26:25 for her first win in a major race since taking two years off after having a baby.
Desisa, 23, was among a group of nine men -- all from Kenya or Ethiopia -- who broke away from the pack in the first half of the race. There were three remaining when they came out of Kenmore Square with a mile to go.
But Desisa quickly pulled away and widened his distance in the sprint to the tape. It's Desisa's second victory in as many marathons, having won in Dubai in January in 2:04:45.
He is the fourth Ethiopian to win the men's race and the first since his training partner, Deriba Merga, won in 2009. Desisa is the 24th East African to win in the past 26 years.
He is the fourth Ethiopian to win the men's race and the 24th East African to win in the past 26 years.
Lisa Larsen-Weidenbach, who won in 1985, is the last American champion; 1983 winner Greg Meyer was the last American man to break the tape.
A year after heat approaching 90 degrees sent record numbers of participants in search of medical help, temperatures in the high 40s greeted the field of 24,662 at the start in Hopkinton. It climbed to 54 degrees by the time the winners reached Copley Square in Boston.
Japan's Hiroyuki Yamamoto was the first winner of the day, cruising to victory in the men's wheelchair race by 39 seconds over nine-time champion Ernst Van Dyk of South Africa. Tatyana McFadden, a Russian orphan who attends the University of Illinois, won the women's race.
Race day got started with 26 seconds of silence in honor of the victims of the Sandy Hook Elementary School shooting.
The 53 wheelchair competitors left Hopkinton at 9:17 a.m., followed 15 minutes later by the 51 elite women. The men were under way at 10 a.m., followed by three waves that over the next 40 minutes would send the entire field of 27,000 on its way to Copley Square.
Last year's race came under the hottest sustained temperatures on record. About 2,300 runners took organizers up on the offer to sit that one out and run this year instead.