Van der Poel attacked on a downhill section of the course, after the race had been whittled down by an attritional day of racing in poor conditions. With 52 kilometres to go, it appeared that it was going to be brought back quite soon, but Pogačar had a mechanical through a corner soon after as he led the chase.
The group reformed as they slowed for the race leader and van der Poel escaped up the road, quickly building a big lead that reached its maximum at three minutes with 20 kilometres to go.
With van Aert setting a hard tempo to put pressure on Pogačar, the gap was starting to be brought back and then the race-leader attacked. The Tour de France winner overhauled some riders who had just launched their own moves, before setting off solo to put time into van Aert.
Van Aert was still a threat to Pogačar's overall lead of 35 seconds entering the stage, with a short, power-focused time trial to come that would conclude the Italian stage race. The Belgian star didn't give and fought his way past the other riders to emerge as third in the impromptu individual pursuit on the road.
Van der Poel was visibly tiring, his lead plummeting as Pogačar surged towards him with van Aert battling behind.
The Dutch star entered the final kilometre with 20 seconds lead, and finished with 10 seconds advantage over the charging overall race leader, with van Aert a further 39 seconds in arrears.
"I was good until the last lap when I was completely empty," said van der Poel. "I don't even know how I got to the finish line today. If I had finished second, it would have been a big disappointment.
"Did I make history? No idea. It feels like that to me, because I can't remember a race where I felt that way at the end. I was just dead in the end. I'm glad I won, but I was really dead."
Van der Poel described his attack in his post-race press conference as trying to warm up from the cold, before elaborating.
"Initially, it was good because we were away with 20 good riders, but they didn't work well together," said van der Poel. "And suddenly I was off on a descent while eating something. At that point, I felt really good so I decided to keep going. Only in the last 15 kilometres did I get really difficult. There was also a lot of wind to ride along here and it was extremely cold."
The Dutch cyclocross and road star suffered through the final run to the line, bringing tension to the race for the stage that seemed impossible as he stretched out to a massive lead with just 20 kilometres to go.
"The last 10-15 kilometres were really hell for me today. I thought he was going to get me," van der Poel said of Pogačar. "I couldn't ride 200 watts anymore, I was completely empty with the cold and the long solo I did. I thought he was going to get me and I'm really happy to be rewarded with the win.
"The body was empty. It was certainly one of the toughest days of my career. I am certainly proud and also very happy that it worked out, because I had very little time left on Tadej."