It made Rupp the first home victor since Moroccan-born Khalid Khannouchi in 2002 and the first American-born champion since Greg Meyer in 1982.
More than a million spectators lined the route to watch and cheer on the runners participating in this year's marathon.
Rupp, the Rio Olympics bronze medalist broke away from Kirui in the final 10kilometres of the race and ensured he finished off the year on high note with a personal best time having finished second at the Boston Marathon earlier on in the year.More news: 5 taco chains with awesome National Taco Day deals
The Chicago Marathon is a long-standing tradition in the IL city where runners across the United States and the world gather to run through 29 neighborhoods and reach the finish line in Grant Park.
Galen Rupp became the first American male runner to win the Chicago Marathon on Sunday since Khalid Khannouchi in 2002. Ethiopia's Tirunesh Dibaba earned the victory in 2:18:31.
Kenya's Abel Kirui was second, 28 seconds behind Rupp. Joan Benoit Samuelson held the previous fastest American woman in Chicago (2:21:21) from October 20, 1985 until Sunday. Her sub-2:21 clocking is a course record for Americans.More news: Las Vegas gunman 'doted' on girlfriend but may have kept secrets
Through 5K in the men's race, there were 26 runners in a lead pack, headed by American Aaron Braun, with all the favourites content on the slow pace, which continued through 10K, projected for a 2:12:30 finish.
In 2016, he came in 3rd out of 1,158 finishers at the Fitzgerald's Lager Run, a five-kilometer (3.1-mile) race in Glen Ridge, with a time of 16:34.
The men split 1:05:49 through the halfway point while the women were not far back in 1:08:48. Khannouchi was born in Morocco so Rupp is the first USA born victor since 1982. Hasay, who had a 2:23:00 marathon PB entering the race, was running 2:17 pace through the quarter-mark of Chicago, her second-ever marathon after finishing third in Boston in April 2017. Brigid Kosgei of Kenya came second and American Jordan Hasay was third.More news: Monday forecast: partly sunny, high 75