Evenepoel had all but confirmed victory after holding off his nearest rival Enric Mas (27) on Saturday's stage 20 and finished the job with ease as he rolled into the Spanish capital flanked by his Quick-Step Alpha Vinyl team mates.
Mas of Movistar settled for second place overall while UAE Team Emirates' Juan Ayuso completed the podium.
Evenepoel is the first Belgian winner of a Grand Tour since Johan De Muynck at the 1978 Giro d' Italia and the youngest Vuelta champion since Angelino Soler in 1961.
"Now it really sinks in, it's really official. Already yesterday the emotions were quite high. We were actually there but we still had to finish the race safe and in a good way," said Evenepoel.
"I didn't have much time to think in Madrid because there it was a really technical course. It was getting more nervous every lap. I'm happy we survived here. It's history for the team, for my country, for myself."
Molano secured the stage win in a thrilling sprint finale, edging out Mads Pedersen (Trek–Segafredo) and UAE Team Emirates team mate Pascal Ackermann on the line.
But the day belonged to Evenepoel, who never relinquished the red jersey after taking the lead on stage six and looked favourite to capture the title after defending champion Primoz Roglic (32), who was steadily closing the gap, withdrew from the race before stage 17.
That left Mas as his sole challenger but the Spaniard could not wipe out the deficit despite a couple of spirited attacks in the final mountain stages.
Evenepoel, who was surprised by fellow Belgian and Real Madrid goalkeeper, Thibault Courtois after the finish, abandoned the 2021 Giro following a crash on stage 17 and failed to medal at the Tokyo Olympics but bounced back strongly earlier this year with a win at Clasica de San Sebastian before claiming two stages at the Vuelta as well as the overall victory.
