The Mexican started third on the grid and Red Bull's strategy worked perfectly, taking the lead after Carlos Sainz pitted and never looked back.
Ferrari's Sainz was second ahead of Championship leader Max Verstappen, while Leclerc had to settle for fourth in a race delayed by an hour due to rain and which featured the safety car and two red flags, the second after Haas' Mick Schmucher crashed at the swimming pool section.
A third career win for Perez was a just reward for a fine drive and proved his doubters wrong, some of whom are reportedly within his own team, having been branded "replaceable" by former driver Jolyon Palmer in the build-up.
The Mexican has had a mixed record in Monaco, podiuming just once, but rose from third on the grid, making the most of the wet conditions to overhaul a frustrated Leclerc.
Sat third overnight, the Red Bull man and his team executed their plan to perfection, pitting first on lap 17 and overcutting Ferrari and when the four cars were back on the road, Perez was first, Sainz second, Verstappen third and a frustrated Leclerc fourth.
That's how it remained as the 32-year-old claimed his third career race win, triumphing by just 1.154s after the race clock expired after lap 65.
With Azerbaijan next on the calendar, Sunday 12th June being race day, could Perez now work his way into the title reckoning? He also triumphed on the streets of Baku last year and would surely be cut from 28/1 for the Championship if he picks up a win on the banks of the Black Sea.
Charles Leclerc qualified on pole for the second straight year but again failed to take advantage.
Last season, the Monagesque driver thrilled his hometown by qualifying fastest, only to miss the race due to a driveshaft issue accrued during a late crash on Saturday.
Leclerc repeated the trick in 2022, with the delayed start hurting him and his frustration could be heard over the team radio.
The 24-year-old was understandably devastated after the race but there were positives to take, with this the first time in his career that he has finished in Monaco.
However, strategy blunders and perhaps a touch of impatience meant his lead dissipated within four laps and he is now 6/4 to win the title.
Of course, being his home race, the Monaco GP means more to Leclerc but he now has to reflect and refocus with Azerbaijan next on the agenda in a fortnight.
The Baku street circuit offers a similar challenge and is one he knows he can get points on, having not finished worse than sixth in his three drives on the banks of the Caspian Sea.
He now trails Verstappen, 8/11 to retain his Drivers' crown, by nine points in the standings but needs to ensure he does not let fears that his 121 start to the season is being wasted affect him.
Monaco is never a race for overtaking and so it proved for Mercedes as George Russell was again their leading man ahead of Lewis hamilton.
The younger of the two Brits moved up a place from his starting position to take fifth, with Hamilton staying eighth.
This is the fifth race in a row that Russell has led his teammate home and he is 16/1 for the title, with the seven-time world champion 25/1.
Is Lewis losing it? That might be premature, but, on current form, it is his 24-year-old colleague who looks the Silvers Arrows' safest bet.