It was a blanket finish behind him as Letsile Tebogo of Botswana took silver by one-thousandth of a second from Briton Zharnel Hughes.
Fourth-placed Oblique Seville of Jamaica was three-thousandths of a second off the podium as all three men clocked 9.88.
Tebogo is the first African to win a world 100m medal, while Hughes, the fastest in the world coming into the championships with 9.83, is the first Briton on the men's 100m podium since Darren Campbell took bronze 20 years ago.
It is the United States though who are firmly top of the sprinting tree again as Lyles' victory makes it four world titles in a row, following four in a row for Jamaica before that.
It had been billed as a wide open final and at 50 metres most of the field were locked together in a line.
Lyles, though forged his way to the front in the last 20 metres, just, and the event’s biggest showman had to delay his celebration until the big screen confirmed his triumph.
"I needed to make sure that I was accelerating and when I was at 60 metres I took the lead," Lyles said.
"I have taken a lot of losses, even in 100m and going to the US trials with COVID I got a bronze medal but a lot of people cut me off right there.
"But I knew what I had to do. I came here for three golds, ticked off one, others are coming.
"The 100m was the hardest one, it is out of the books. I will have fun with the event I love now."
The two-times world champion in the 200m will now go for the sprint double, last achieved by Usain Bolt in 2015, before hoping to sign off with a win in the sprint relay.
Hughes, who was disqualified for a false start in the Tokyo Olympics final, was delighted with his medal to cap a season where he has captured the British 100 and 200m records that had both stood for 30 years.
"I'm super, super grateful right now," he said. "I wanted the gold, but I'm happy to leave with a medal.
"When they had a false start in the semi, it made me sit in my blocks a bit. I thought I's got Lyles. When I saw the results and saw Tebogo's name I thought 'where did he come from?'"
The defending world champion Fred Kerley of the US failed to qualify for the final after running 10.02 in his semi-final.
