The victory continues a strong start to the season for the Slovenian as he prepares to defend his Tour de France title.
"What a fantastic start to the season," Pogacar said.
"This is one of the biggest one-week races."
After placing fourth in the concluding time trial, Pogacar finished 1 minute and 3 seconds ahead of Wout van Aert in the overall standings of the sea-to-sea race.
Slovenian Pogacar built his victory by prevailing in the only mountain top finish of the race, then extending his overall lead over Van Aert in Sunday's fifth stage.
The 10km final-stage time trial in San Benedetto del Tronto was won by Belgium's Van Aert, 26, who surprisingly beat defending world time trial champion Filippo Ganna of Ineos.
The Italian has not been beaten in a time trial since taking the rainbow jersey in Italy last year.
Mikel Landa finished third in the overall GC standings, 3:57 behind. Egan Bernal, the 2019 Tour winner, finished fourth, more than 4 minutes behind Pogacar.
Christopher Hamilton of Team DSM was the best-placed Australian in the final GC placings in 29th position, while Michael Hepburn of Team Bike Exchange managed a ninth-place finish on the final stage