Sinner, who took over as the title favourite after Week 1 exits by Novak Djokovic and Carlos Alcaraz, is the only man remaining in the field with a Grand Slam trophy.
He won his first at the Australian Open in January by beating Medvedev in the final in five sets after dropping the first two.
And he gained revenge on Wednesday for his loss to Medvedev in the Wimbledon quarter-final in July.
Daniil Medvedev makes a return against Jannik Sinner. (AP PHOTO)
As reflected by the score, this matchup was unusually topsy-turvy as they took turns dominating a set at a time.
First, it was Sinner who was superior. Then that role was played Medvedev. Then Sinner regained the upper hand in the third. In the fourth, from 3-all, Sinner surged, saving a pair of break points, then breaking Medvedev to lead 5-3.
"It was very tough, we know each other quite well, we played in Australia and London, so we knew it was going to be very physical," Sinner said.
"It was strange the first two sets, because whoever made the first break then started to roll."
The key: Sinner won the point on 28 of his 33 trips to the net, including 9 of 11 on serve-and-volley approaches.
"We tried to work really hard on this aspect of the game," Sinner said. "Trying just to mix up the game."
Sinner - the 23-year-old from Italy who was cleared in a doping case less than a week before the US Open started after testing positive twice for trace amounts of an anabolic steroid in March - will go up against rising star Jack Draper on Friday for a berth in the title match.
That day's other semi-final will be world No.12 Taylor Fritz v world No.20 Frances Tiafoe in the first all-American men's matchup at this stage at a major in 19 years.
The 22-year-old Draper reached his first grand slam semi-final - and became the first British man to get that far at Flushing Meadows since Andy Murray won the 2012 trophy - by overwhelming No.10 Alex de Minaur 6-3 7-5 6-2 as the Australian appeared to struggle with a hip injury flare up.
Jack Draper at full stretch in his win over Alex de Minaur. (AP PHOTO)
Draper has won all 15 sets he's played so far, but things figure to get tougher against Sinner.
"This is not kind of like an overnight thing for me. I've believed for a long time that I've been putting in the work and doing the right things, and I knew that my time would come," said Draper, whose upper right leg was taped by a trainer after he felt something at the end of the first set.
"I didn't know when it would be, but hopefully from here, I can do a lot of amazing things. I'm very proud of myself."
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