It is a first title of the year for Sinner, who had his Australian Open title defence ended by Djokovic in a thrilling five-set semi-final in January.
Sinner also extends his head-to-head record against Medvedev, having won nine of their past 10 meetings.
Despite the loss, Medvedev will re-enter the top 10 when the rankings are updated on Monday.
The former US Open champion almost missed the tournament, having been stuck in Dubai because of the ongoing conflict in the Middle East.
After arriving in the USA, Medvedev showed why he was previously at the top of the men’s game, with a fine semi-final victory over world number one Carlos Alcaraz.
However, it was Sinner who edged the tight moments on Sunday, helped by his imperious serve.
Sinner won 43 of 47 first-serve points, hit 10 aces and won 60% of points behind his second serve to remain in control of the match.
Medvedev saved the only two break points of the final and came close to forcing a third set when he went 4-0 up in the tie-break.
However, Sinner reeled off seven points in a row to close out the match and win back-to-back Masters 1,000 titles without dropping a set.
Elsewhere, world number three Djokovic has withdrawn from this week’s Miami Open with injury.
The Serb great has won the title six times and finished runner-up to Jakub Mensik last year.
However, the 24-time Grand Slam champion said a right shoulder injury had stopped him competing at the hard-court event, which begins on Monday.