The second-seeded Russian player dug deep to stop Djokovic from mounting another comeback as he prevented the top-ranked Serb from claiming his first title of 2022.
The 24-year-old Rublev looked fitter in their third set as he closed out the win in 2 hours, 24 minutes.
Djokovic — who is 10 years older than Rublev — appeared affected by the effort he put in to level the match in the second-set tiebreaker.
Djokovic had already come back from a set down in each of his three matches at his hometown tournament, defeating Laslo Djere, Miomir Kecmanovic and Karen Khachanov on his way to the final in what were only his fifth, sixth and seventh matches of the year.
The 20-time Grand Slam champion opened his clay-court season with a surprising loss to Alejandro Davidovich Fokina at the Monte Carlo Masters the previous week, his first match since being eliminated in the quarterfinals of the Dubai Championships in February.
Dubai was his first tournament of the year after he was barred from playing at the Australian Open because of his unvaccinated status, which also prevented him from playing tournaments in the United States last month.
Rublev, who dropped only one set as he eliminated Jiri Lehecka, Taro Daniel and Fabio Fognini on his way to the final, has now equaled Rafael Nadal‘s mark of three tour-level titles in 2022, after wins in Marseille and Dubai in February.