Desisa, 23, made a push over the final half mile of the 26-mile, 365-yard course in pulling away from countryman Gebregziabher Gebremariam and Kenya's Micah Kogo to win the 117th running of the marathon in Boston.
Desisa covered the course in 2 hours, 10 minutes, 22 seconds, which was 5 seconds ahead of Kogo and 6 up on Gebremariam. U.S. runner Jason Hartman was fourth in 2:12:12.
Jeptoo, 32, who won the Boston Marathon in 2006, was first in the women's section by 33 seconds. She finished in 2:26:25, which was about 3 minutes slower than her 2006 winning time.
Meseret Hailu of Ethiopia was second while Kenyan Sharon Cherop, who was the 2012 race winner, took third. Shalane Flanagan was the top American finisher in fourth.
It was the third consecutive year and 10th time in 14 years a Kenyan won the women's race.
Japan's Hiroyuki Yamamoto won the men's wheelchair section in 1:25:33 while American Tatyana McFadden won the women's wheelchair race in 1:45:25.