Ryan Hall and Abdi Abdirahman finished second and third, and the trio embraced before turning their sights to London.
The top American men's and women's distance runners competed in Houston for three Marathon spots on each team that will represent the U.S. at the Summer Games.
Shalane Flanagan won the women's Olympic trial. Desiree Davila finished second and Kara Goucher was third.
The 36-year-old Keflezighi covered the course in a personal-best 2 hours, 9 minutes and 8 seconds. He qualified for his third games, returning after winning silver in the 2004 marathon in Athens.
Keflezighi is the first runner to win the New York marathon (2009) and the U.S. Olympic trial. He's also the oldest winner of the trial, putting together an impressive race just 70 days after finishing sixth in New York in November.
Keflezighi missed three weeks of training after that race after developing an infection in his left foot, the result of leaving a nasal strip in his shoe. He remembered to wear the nasal strip on his nose Saturday, and he had broken away from Hall by Mile 24.
Hall's time was 2:09.30 and Abdirahman finished in 2:09.42.
Dathan Ritzenheim, second to Hall in 2008, crumpled to his knees and cried as he finished fourth, 13 seconds behind Abdirahman.
The 29-year-old Hall won the 2008 marathon trial in a record 2:09.02. He was back in one of his favorite cities to run, where he won the 2007 U.S. Half Marathon championship in an American record time of 59:43.
The 33-year-old Abdirahman will compete in his fourth Olympics. He qualified in the 10,000 meters in the previous three games.
Flanagan, 30, set a trials record on the women's side, finishing in 2:25.38. It was her second marathon and first since she was the runner-up in New York in 2010.
The 28-year-old Davila, the runner-up in Boston last year, finished in 2:25.55. She'll make her Olympics debut.
The 33-year-old Goucher trains with Flanagan in Oregon and finished Saturday's race in 2:26.06. She'll compete in her second games after running in the 5,000- and 10,000-meter races in Beijing.
The weather was ideal, with the races starting under a clear sky and a temperature of 40 degrees.
Hall went straight to the front from the opening gun, and ran the first mile in 4:52. Mo Trafeh and Keflezighi matched him stride-for-stride as the lead pack wound through downtown Houston.
Keflezighi passed Hall in Mile 8, and looked over his shoulder. Hall retook the top spot, and the men's lead group had a 40-second lead on the rest of the pack by Mile 9.
The men's lead group was down to four runners -- Hall, Abdirahman, Ritzenheim and Keflezighi -- through 17 miles. Abdirahman waved his arms, encouraging the fans lining the streets to cheer, as Ritzenheim dropped off the pace.
Abdirahman fell back, leaving Hall and Keflezighi alone at the front by Mile 22. Keflezighi then stretched the gap from Mile 24.
Keflezighi looked over his shoulder in the final mile and pumped his right fist to acknowledge the cheering crowd. Someone handed him an American flag near the finish and he waved it as he crossed the finish line.
Flanagan and 2008 Olympian Magdalena Lewy Boulet started the women's race side-by-side. Davila and Amy Hastings had moved to the front by the second mile, when the runners began the first of three circuits around an 8-mile loop. Davila and Hastings were roommates at Arizona State.
The women's lead group reached the midway point of the race in just over an hour and 13 minutes. Hastings fell back, then surged to the lead by the Mile 17 marker. Flanagan and Davila then moved to the front, with Goucher keeping pace until the final mile.
On Sunday, 28,000 runners will take to the streets for the 40th anniversary of the Chevron Houston Marathon.
In honor of the Houston Texans playoff game, the marathon committee is asking runners and spectators to wear Texans colors.
That means you can expect to see a sea of red, white and blue on the streets.
The Texans cheerleaders will be at the finish line, and we've learned the Texans will launch a line of running gear in the coming months.
Several streets near Discovery Green will be closed Sunday morning. There will also be closures on Elysian, Montrose, Weslayan, Memorial, Allen Parkway and others.
ABC13 is your home for Sunday's coverage of the Chevron Houston Marathon and Aramco Half-Marathon.
On the air, we'll be live from 7-10am. At the same time, two different cameras will be streaming the race live on abc13.com. Then, watch Tom Koch wrap everything up Sunday on The Finish Line at 10:35pm.
The Associated Press contributed to this report.