The 31-year-old Movistar rider spent most of the 186-km stage in a group alongside Primoz Roglic, Felix Gall and Richard Carapaz - the only men who could deny him the red jersey - and simply refused to crack.
Looking perfectly in control up the steep and winding final 9-km climb to Collado del Alguacil, Mallorcan rider Mas comfortably protected the one minute 37 seconds advantage he held over Slovenian Roglic after 19 stages and even stretched his lead at the climax.
With only Sunday's ceremonial stage around the city of Granada to come, Mas looks certain to become the first Spanish rider to win the Vuelta since Alberto Contador 12 years ago.
Veteran Mikel Landa (Soudal–Quick-Step) made it a perfect day for the home nation as he powered away from the breakaway group up the Collado del Alguacil to take the stage, his first victory since 2021.
Mas inherited the red jersey when overwhelming race favourite Tadej Pogacar crashed out on stage eight.
Since then he has barely put a pedal stroke out of place to finally shake off the tag of one of the best Spanish riders never to have won a Grand Tour, something he shares with Landa.
There was still the 186-km stage 20 to survive, though.
A relentless day in the mountains featured four big climbs, including twice up the Puerto de El Purche, before the finale on the brutish Collado del Alguacil, a 17-km climb with the last 8.3km averaging a leg-stinging 9.8%.
Former Olympic champion Carapaz attacked throughout the day with his usual panache, and Gall looked a threat to Mas. But the Spaniard was never flustered, and when he dropped four-time Vuelta champion Roglic in the final kilometres he knew the general classification battle was won.
"It's the first time in my life I feel like this," he said.
"To be honest, I was just counting the kilometres. My feeling was super. The team did a super good job again. I won because the team did everything. Thank you."
With just the 21st stage around Granada left, Mas holds a 2:15-second lead over Roglic, with Austria's Gall 2:44 in arrears.