Jeptoo, 29, finished the 26.2 mile race in 2 hours 25 minutes 7 seconds, or just 5:33 minutes per mile.
She overtook Bronx resident Buzunesh Deba, who was in the lead for much of the race, and finished with a comfortable :48 second lead.
The men's race was much tighter with Mutai, 32, breaking away in Mile 20 with a brisk 4:46 mile. He finished with his second New York title in 2:08:24, or 4:55 minutes per mile.
More than a million people lined the streets of New York City on a chilly Sunday morning cheering on some 47,000 runners taking part in the annual 26.2-mile marathon.
The New York City marathon is back under tight security after being canceled last year in the aftermath of Superstorm Sandy that ravaged much of the East Coast.
Just five months later, terrorist attacks at the finish line of the Boston Marathon killed three people and wounded more than 260.
New York City police said no threats to Sunday's marathon have been identified but they stepped up security measures and police presence by land, air and sea.
"This will be the best-protected race that they can enter," NYC police commissioner Raymond W. Kelly said in a message to runners.
"There are no guarantees in our post-9/11 world, but we’re doing everything we reasonably can to protect the runners and the spectators and have this be a safe and enjoyable event."
The race was being patrolled by helicopters, police boats and officers carrying radiation detectors. Dozens of bomb-sniffing dogs were deployed to the start and finish lines, reports the New York Times.
The extra security didn't seem to dampen the mood of either the runners or the spectators who gathered to watch the race begin.
"I've been tossing and turning, so I know that there are a lot of excited people," retired tennis ace John McEnroe, who lives on Central Park, told AFP.
"There's a lot of electricity in the air."
Having helped to train six runners, he said there was something extra special about this year's marathon.
"I know year in and year out how excited people get and how much it means to the city," he said.
"Especially after what happened last year, so it's just got an extra special significance."
Camilla Michelle Singh, helping her three musician sons set up for a live performance along the route, told AFP that she welcomed the extra security.
Her boys aged 11 to 16, who have played for TV show "America's Got Talent," were bitterly disappointed when they couldn't perform last year because the race was canceled.
Instead, the Singhs hosted for two months families who lost everything in Hurricane Sandy.
"The marathon means a lot to us. It's exciting. It's our culture, our country," she said.