The Russian's last appearance in a Tour-level championship match was 13 months ago, when he beat Zverev in straight sets at the Shanghai Masters.
This was a more competitive affair, at least in the opening hour, but it was Medvedev who triumphed 5-7 6-4 6-1 to lift his eighth career title.
He is the fourth Russian to win the tournament, after Marat Safin, Nikolay Davydenko and Karen Khachanov.
Medvedev had lost five times in eight matches in the build-up to this event but has found form on the hard courts of the French capital, dropping just one set en route to the final.
Zverev, who dispatched Rafael Nadal in straight sets in the semi-finals, continued that form in the first set on Sunday as he missed his mark just five times on his first serve.
Medvedev kept pace until game 12, when he saved two break points but not the third, Zverev letting out a roar as he took a step towards a third Tour title in a row.
Each man was backing up their serve with authority, although Zverev saved four break points in the third game of the second set as Medvedev began to find more rhythm from the baseline.
The world number five got his breakthrough at the next time of asking before holding to love to level the match, as Zverev's form began to falter.
The German seemed suddenly bereft of confidence as he surrendered his opening service game to love, and a double break soon put Medvedev in control.
A double fault from the German on the second match point gifted an impressive win to Medvedev, who will feel full of confidence ahead of the ATP Finals in London.