Under almost ideal weather conditions, 40,000 runners took part in Sunday's race, the 40th annual for Chicago.
Last year's victor Abel Kirui of Kenya was placed second while marathon record holder Dennis Kimetto did not finish.
Ethiopian Tirunesh Dibaba pushed toward a course-record pace nearly from the start to win the women's side of the Marathon in 2:18:31.
Rupp made his move in the 24th mile and there was no catching him as America's wait for a first male victor of the race since Khalid Khannouchi finally ended.
Rupp, who took 2012 Olympic silver at 10,000m, made his charge with three miles remaining and no one had a response.
Fearnley has never finished lower than second in Chicago, recording five wins and two runner-up finishes before Sunday's result. "It feels tremendous. I feel so great I was able to pull it out". Brigid Kosgei of Kenya came second and American Jordan Hasay was third.
But ultimately she came up slightly short of the course record.
At 30km, the pace was pushed a bit higher led by Kirui in 1:48.33 while Kenyan Stephen Sambu fell off to the back.
The four-time IAAF World Cross Country champion, started opening a small gap between her and Kosgei who slowed down after covering 30km in a time of 1:38.50. Previous year in Rio, Dibaba was third in the 10,000.
It crowned a superb season for the 32-year-old after she followed second place at the London Marathon in 2:17:56 - the fifth fastest time ever - with a 10,000m silver medal at the World Championships. This was her second career marathon.
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