The 21-year-old was expected to face a close challenge from Andre De Grasse, but the Canadian was left trailing in third as Lyles laid down a serious marker ahead of September's World Championships in Doha.
"Oh my God, would it be crazy if I said yes?," said Lyles when asked if he expected to run so fast.
"The worlds -- I've been waiting for this since 2017, for so long, but I have no pressure as I have never participated in a big championship."
Only world-record holder Usain Bolt (19.19sec), his fellow Jamaican Yohan Blake (19.26sec) and four-time Olympic gold-medal winner Michael Johnson (19.32sec) have run quicker.
Lyles will now have the US Track and Field Championships, which run from July 25-28 in Iowa, in his sights.
"I was even disappointed that the trials are postponed until July (from June)," he added. "It makes we wait even more, and I want to show that I'm the best."
Running in lane 7, Lyles seized a clear lead coming out of the bend and was never going to be caught in the final 100m.
Ecuador's Alex Quinonez snatched a surprise second place from lane 8, ahead of De Grasse (19.92sec), running 19.87sec.
Two-time Olympic champion Shelly-Ann Fraser-Pryce powered to a dominant victory in the 100 metres to confirm her return to the upper echelons of sprinting, while reigning world champion Justin Gatlin won the men's race.
The 32-year-old Jamaican, on the comeback trail after taking time away from the sport to give birth to her son Zyon, clocked 10.74 seconds to beat European champion Dina Asher-Smith into second.
Fraser-Pryce had already impressed when finishing second at the Jamaican trials last month, managing the same time (10.73sec) as winner Elaine Thompson.
She won the 100m gold medals at both the 2008 and 2012 Olympics, before having to settle for bronze behind compatriot Thompson in Rio de Janeiro three years ago.
Fraser-Pryce will be a contender for a medal at the worlds if she can maintain this kind of form.
Her time was only 0.02secs slower than Marion Jones' 21-year-old meeting record.
Britain's Asher-Smith, 23, ran a season's best time of 10.91sec to beat world silver medallist Marie-Josee Ta Lou (10.93sec) into third.
American veteran Gatlin proved his is still capable of defending his world 100m title later this year with a second consecutive Diamond League win.
The controversial 37-year-old, who has twice served doping bans in his career, claimed victory in 9.92sec, having run 9.87sec to triumph in Stanford last weekend.
The 2004 Olympic champion beat fellow countryman Michael Rodgers (10.01sec) and Canada's Michael Rodgers (10.07sec).
"I feel good, I feel strong," said Gatlin.
Earlier on Friday, Bahrain's Salwa Eid Naser made it four women's 400-metre victories from as many Diamond League races this year.
Nigerien Aminatou Seyni pushed her all the way, but Naser won in 49.17sec, smashing the previous Lausanne record of 49.45sec set by Marie-Jose Perec in 1996.
Seyni was a relative unknown just two weeks ago, but has since improved her personal best by an incredible one-and-a-half seconds.
"My race was very good," said the 22-year-old.
Ethiopian Hagos Gebrhiwet suffered an embarrassing mishap during men's 5,000 metres, crossing the line with his arms raised in celebration -- but with a lap still remaining.
His compatriot Yomif Kejelcha took full advantage, showing little sympathy to take the victory in 13 minutes and 0.56 seconds as Gebrhiwet was forced to settle for 10th.
Kenya's Timothy Cheruiyot edged out Norwegian rising star Jakob Ingebrigtsen to win the 1,500m in a world-leading time of 3min 28.77sec.
There were also wins for Olympic champion Caterine Ibarguen in the women's triple jump and Spain's Orlando Ortega in the men's 110m hurdles.
Six men ran sub-1min 45sec times in a remarkable 800m race won by Commonwealth gold medallist Wycliffe Kinyamal of Kenya.