Two years after losing the lead late in the 42.1km race, Kamworor held off compatriot Wilson Kipsang to win in an unofficial time of 2hrs 10mins 53secs.
Flanagan's final time of 2:26:53 was nearly a full minute ahead of Keitany's, who finished with 2:27:54.
American women had not won in NY since Miki Gorman claimed her second consecutive title in 1977. "This is the moment I've dreamed of since I was a little girl".
The marathon was run against the backdrop of heightened security after a terrorist attack earlier in the week killed eight people on a bike path in the city.
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American running great and 2009 NY victor Meb Keflezighi completed his 26th and final marathon, collapsing as he crossed the finish.
Flanagan, who had never won a major marathon, clocked two hours, 26 minutes 53 seconds for the stunning victory at the age of 36. New York City is also where her marathon career began.
It was Flanagan's first marathon of the year following a left hip injury in January. She had blown away the field here a year ago, winning by a margin (3 minutes 34 seconds) not seen in the women's race since 1980.
Behind her, but fading fast, Mary Keitany was chasing history, too: The 35-year-old Kenyan had won this race three times in a row.
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After taking the lead in the 23rd mile, the 24-year-old 2015 NY runner-up had to contend with Kipsang, whose final push brought him ever so close to his countryman.
In the wheelchair event, the Swiss dominated with Manuela Schar tops among women and Marcel Hug finishing first among the men.
Hug, who won last year's race by sixth hundredths of a second, finished over two minutes clear of Canada's Josh Cassidy to win his third NY title.
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