Lyles, who won the 100m and 200m titles at last year's world championships in Budapest, will run the shorter sprint in the British capital in his continuing bid to set himself up as the true successor to now-retired legend Usain Bolt.
But the American will be up against Britain's Anguilla-born Zharnel Hughes, who won bronze behind him in Hungary, and the dangerous duo of world silver medalist Letsile Tebago of Botswana and South Africa's Akani Simbine.
"I'm looking forward to London, I feel it's going to be special," said Hughes, who was disqualified from the 100m final at the Covid-delayed Tokyo Olympics won by Italy's Marcell Jacobs.
"The fact it's the last Diamond League before the Olympic Games, it's going to be stacked and I want to lay something down there."
Hughes co-stars alongside Lyles in the Netflix docu-series "Sprint", but said he hadn't realised how much his US rival talked about him.
"I didn't really know he said that much about me until I saw the preview and I realise he said a lot," said Hughes.
Psychological games
"I was like, 'this guy can talk!' I knew he talked, but I didn't know he talked that much. Obviously me being a competitor, it raised all the red in me. I was like, 'this guy, man! Shut up.'
"My girlfriend said 'don't try to let it get to your head. He's saying these things so you guys can be thrown off psychologically'. So for me I use that desire, that red in me, and I try to put it out on the track.
"I'm looking forward to actually sitting down and hearing all the things that he had to say. It's just the perfect timing leading up to the Olympic Games. I will see him in London and we'll meet there - but I'll talk with the spikes.
"He just has a loose mouth, but I guess that's how he gets his confidence. At the end of the day he's performing as well, so I have to give him credit."
Apart from Hughes, British interest will come from the Carl Lewis-coached Louie Hinchliffe, who won the 100m at the highly competitive NCAA championships in a personal best of 9.95sec before snatching the British title too.
The meet in London, in the stadum used for the 2012 Olympics and now home to Premier League club West Ham United, comes just six days before the Paris 2024 opening ceremony and there is a galaxy of talent on show outside of the men's 100m.
Femke Bol will compete in the women's 400m hurdles fresh from smashing her own European record by half a second with victory in 50.95sec in La Chaux-de-Fonds, Switzerland.
She became just the second woman after US Olympic champion Sydney McLaughlin-Levrone to break the 51-sec barrier.
A loaded women's 800m sees Olympic gold medal hope Keely Hodgkinson up against British teammates Laura Muir, Jemma Reekie and Georgia Bell, as well as Uganda's 2019 world champion Halimah Nakaayi.
And American Ryan Crouser fine-tunes his preparations for his bid for a third Olympic shot put gold as he takes on teammate Joe Kovacs, New Zealand's Tom Walsh and Italy's new European champion Leonardo Fabbri.
