Lyles celebrated his 21st birthday in style, the wannabe rapper scorching to victory in 19.65 seconds, the fastest run this season and a meet record.
World champion Ramil Guliyev of Turkey finished second in 19.99, but Lyles was well clear of the field in perfect, balmy conditions at Monaco's Louis II stadium.
"It was a great race, especially improving the meet record," said Lyles, a notoriously bad starter.
"I had the same (good) start as I had in Eugene and I felt it. It gives me confidence in what I can do next."
It was another gun-to-tape win for Semenya, who is challenging the IAAF over controversial new rules track and field's ruling body plan to introduce on high testosterone levels in female athletes.
She shot out past even the pacesetters and with Czechoslovakian Jarmila Kratochvilova's 1983 world record of 1:53.28 seemingly in imminent danger, Semenya blasted through the first lap in 55.76sec and increased her lead over the chasing pack as she lengthened her stride down the back straight before rounding the final bend.
The 27-year-old, double Olympic champion (2012, 2016) and three-time world champion (2009, 2011, 2017), eventually tied up slightly as she pushed through to the line in 1:54.60, also a meet record.
"It was just fantastic!" beamed Semenya. "Only the last 100m were a little off for me.
"Today I wanted to break 1:54 but maybe next time. I wasn't thinking about the world record and it wasn't on my mind."
But it was a relatively unknown Kenyan, Chepkoech, who stole the plaudits by setting a new 3000m steeplechase world record.
Chepkoech, 27, ran 8min 44.32sec to shatter the previous best set in 2016 by Kenyan-born Bahraini Ruth Jebet, whose name headlined an Athletics Integrity Unit report released earlier Friday into alleged doping.
Olympic champion Jebet had run 8:52.78 before Chepkoech, aided by a couple of pacemakers, shot around more than six seconds faster, her remarkable effort also smashing her own previous personal best by more than 15 seconds.
"I wanted to break the world record, that was the plan from the start of the season," she said.
"I felt strong during the race and was thinking I might be able to break 8:50, but not at all dreaming about 8:44.
"It's a great feeling to bring the world record back to Kenya."
Marie-Josee Ta Lou racked up a fifth win of the season in the Diamond League by winning the 100m in 10.89sec ahead of Ivorian compatriot Murielle Ahoure (11.01sec), with Jamaica's double Olympic sprint champion Elaine Thompson taking third (11.02).
"It's an incredible year for me," said Ta Lou, a double world silver medallist in 2017. "I'm performing really regularly and the goal was to go under 10.90 and I did just that so I'm super happy."
Setting the scene for a night of unforgettable track action, Shaunae Miller-Uibo shattered the Bahamas and Diamond League records with a blistering 48.97sec in the opening 400m, Bahrain's Salwa Eid Nasr coming in second in an Asian record of 49.08.
"I'm so happy I got this sub-49 I was waiting for," said Miller-Uibo, who became only the fifth female in history to have gone sub-49 in the 400m and sub-22 in the 200m.
"The next goal is to remain consistent on this level and long term another barrier is 48 seconds," with the world record of 47.60sec set by East German Marita Koch back in 1985.
That scintillating start to action was followed up by Botswana's Nijel Amos running a season-topping 1:42.14 in the 800m, and then Timothy Cheruiyot of Kenya also setting a world lead (and personal best) of 3:28.41 in the 1500m.