The pair broke away from the main peloton 40km from home accompanied by Australian Lucas Plapp, who took the virtual lead during this stage ensuring the big guns hunted the trio all the way to the line.
The 180km were covered in a mere 4hrs 1min and 8sec of pulsating racing, with the peloton arriving just 29sec adrift despite the hills and the gravel.
This sixth of 21 stages then was raced just as frantically as the previous five on a nervy Giro d'Italia still led by the Slovenian Tadej Pogacar.
The race leader had been expected to attack again, but sounded relieved after the race.
"That's another stage ticked off, frankly I'm just glad it's over. It was nice but Ineos rode so hard on the gravel it just never stopped," said Pogacar.
The white gravel roads that give the Tuscany wine their taste also feature in the Strade Bianche classic, won by Alaphilippe in 2019, and almost delivered the Quick Step veteran a new triumph.
Two time world champion Alaphilippe was unbowed claiming he was still confident of a stage win on this Giro, and also praised the victor.
"The best man won, he was wilier and he was faster," said the 32-year-old.
Pogacar won on the same roads this year and on Thursday proved reluctant to allow his overall leader's pink jersey slip and his team relentlessly chased the escape trio, likely denying Alaphilippe a win as the 24-year-old Sanchez closed out faster.
"It was an insane day. The race was out of control the whole stage. It was ridiculous for the first 80km," third placed Plapp said.
The winner echoed the same sentiment.
"It's crazy. I don't have words. All day full gas," said Sanchez. "I never imagined winning the stage."
Pogacar leads Geraint Thomas by 46sec and Dani Martinez by 47 ahead of Friday's long 40km individual time trial that culminates with a climb to the Perugia finish line.
"It's an interesting route. I'm not sure how to take it yet, I just want to feel good on the bike, have good legs. Let's see tomorrow," Pogacar said.