In the last sprint before the Olympics, Lyles was relatively quick out of his blocks and tore down the track at London Stadium to win in 9.81 seconds.
Importantly, he easily held off a clutch of rivals he would expect to come knocking in Paris and now looks like the sprinter to beat in the French capital.
"That was fun," said Lyles. "I could have had a better start. The transitions were great and coming away with a personal best.
"I wanted a faster time but I had the wind. After building my confidence and getting through 2021, this has been what I prayed for and what I wanted."
Turning to the Paris Olympics, Lyles added: "I'm going to win, it's what I always do. I'm getting faster every week."
Once the American, who won the 100-200m golds at the Budapest world championships last year, got going, there was no doubt he would win.
South African Akani Simbine timed a season's best of 9.85sec in second, while Botswana's Letsile Tebogo rounded out the podium in 9.88sec to match his own national record.
British champion Louie Hinchliffe, the winner of this season's NCAA championships, was fourth in 9.97sec, while Zharnel Hughes had to be content with sixth (10.00) behind Jamaica's Ackeem Blake (9.97).
"It's OK. I'm not happy with the result but it's not bad, it wasn't my worst run," Hinchliffe, coached by US track and field legend Carl Lewis, told BBC.
"I can work on the start, I looked well out of it. Maybe some nerves, it's my first time here. Some way to go."
Hughes, who won bronze behind Lyles in Hungary, co-stars alongside the American in the Netflix docu-series "Sprint", but said pre-race that he had not realised how much his US rival talked about him.
Hughes had vowed to silence Lyles' "loose mouth", but was never in contention as the American ripped away for victory in front of 58,000 fans at the stadium used for the 2012 Olympics and now home to Premier League club West Ham United.
