Having said beforehand that the mountains weren't a focus for him, Dumoulin surprised everyone by attacking off the peloton with three kilometres to go and crossed the line nearly 10 seconds ahead of his general classification rivals.
Vincenzo Nibali and Mikel Landa were the big losers on the stage, finishing several seconds behind the likes of Alejandro Valverde (Movistar) and Rigoberto Uran (Cannondale).
Heading into the final climb up to Roccaraso, Lotto-Soudal duo Wellens and Pim Ligthart held a sizeable gap with their three breakaway companions, allowing the former to lay an early and decisive attack.
The main action was going on five minutes down the road, however, as the general classification contenders tried not to cede any time to each other.
Jakob Fuglsang attacked off the front with 13km to go to help his Astana teammates and leader Nibali. With the Dane within touching distance of the maglia rosa at the start of the day, pink jersey holders Giant-Alpecin were forced into action in the chase.
Movistar, Team Sky and Tinkoff helped Giant-Alpecin in their chase as Fuglsang and Kanstantin Siutsou (Dimension Data) increased their lead to 50 seconds over the peloton.
With around 3.5km to go on the mountain, race favourite attacked off the peloton with an attempt to join Fuglsang up the road. Team Sky reacted to bring Landa back as the peloton stretched out into a line as Nibali was brought back.
Giro d'Italia 2016: The contenders
As soon as Nibali was brought back pink jersey holder Dumoulin sped off the front, followed by Domenico Pozzovivo (Ag2r La Mondiale) and Ilnur Zakarin (Katusha).
In no time the three riders caught Fuglsang and Siutsou just as Wellens crossed the line for the stage win for his seventh professional win and Lotto's second successive stage win.
Ninety seconds later, Fuglsang won the battle for second place, with Dumoulin trailing Zakarin in fourth place to miss out on any bonus seconds.
Dumoulin increased his lead in the general classification, though, now sitting 26 seconds ahead of Fuglsang, but crucially 41 seconds up on Valverde and 47 seconds ahead of Nibali with Sunday's time trial only likely to see that lead grow more.
Giro d'Italia 2016 stage six, Ponte - Roccaraso (Aremogna) (157km)
1. Tim Wellens (Bel) Lotto-Soudal, in 4-40-06
2. Jakob Fuglsang (Den) Astana, at 1-19
3. Ilnur Zakarin (Rus) Katusha, st
4. Tom Dumoulin (Ned) Giant-Alpecin, at 1-22
5. Kanstantsin Siutsou (Blr) Dimension Data, 1-24
6. Domenico Pozzovivo (Ita) Ag2r La Mondiale, st
7. Esteban Chaves (Col) Orica-GreenEdge, at 1-29
8. Rigoberto Uran (Col) Cannondale, at 1-33
9. Rafal Majka (Pol) Tinkoff, st
10. Alejandro Valverde (Esp) Movistar, at 1-36
Overall classification after stage six
1. Tom Dumoulin (Ned) Giant-Alpecin, in 24-22-15
2. Jakob Fuglsang (Den) Astana, at 26s
3. .Ilnur Zakarin (Rus) Katusha, at 28s
4. Bob Jungels (Lux) Etixx-Quick Step, at 35s
5. Steven Kruijswijk (Ned) LottoNL-Jumbo, at 38s
6. Alejandro Valverde (Esp) Movistar, at 41s
7. Diego Ulissi (Ita) Lampre-Merida, st
8. Esteban Chaves (Col) Orica-GreenEdge, at 44s
9. Vincenzo Nibali (Ita) Astana, at 47s
10. Kanstantsin Siutsou (Blr) Dimension Data, at 49s
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