The 27-year-old American had run a 400m in Atlanta in April, but was yet to compete over the 100 or 200m this season.
But he showed no rustiness on a track where his one previous appearance, in 2020, saw him clock a sensational 19.46 seconds.
Lyles, in lane seven, delivered a perfectly-executed bend to win in 19.88sec.
Lyles' season and European debut in the half-lap race saw him line up against Botswana's Olympic 200m champion Letsile Tebogo.
It was the duo's first race since that final in Paris last summer when a Covid-struck Lyles claimed bronze.
Tebogo had headed to Monaco as the sprinter to beat. He set the fastest time of the season over 200m in Eugene on Saturday, in 19.76sec, having recovered from a poor start to the season.
He clung on to Lyles down the back straight, but the American's finishing power proved too much for the Botswanan, who finished second in 19.97sec.
While Tebogo calmly walked onto the track, applauding the crowd as the lights strobed and Metallica's 'Enter Sandman' belted around the stadium, Lyles bounced on, raising his arms to egg on the exultation.
It was the same at the Paris Olympics, but this time at Monaco's Stade Louis II, the outcome was different.