The top-seeded partnership, which won their first tournament together at Wimbledon in July, pushed their team record to an unblemished 10-0 with the win over the number three seed.
The milestone comes just 24 hours after she won the mixed doubles title at Flushing Meadows with Britain's Jamie Murray. "She's such a great player, you know, a huge champion of the game".
Third seeds Chan and Venus lost the first set 6-1, but then rallied to claim the second 6-4 to take the final to a super tiebreak, but the top seeds proved too strong as they edged the decider 10-8 after one hour, nine minutes to add the US Open to the title they won at Wimbledon two months ago.
Martina Hingis and Yung-Jan Chan embrace after their win against Lucie Hradecka and Katerina Siniakova.
She won the 1997 US and Australian Open and Wimbledon singles titles and the 1998 and 1999 Australian Open singles crowns as well as seven mixed doubles titles, including this year's Wimbledon and US Open mixed titles.
Asked why his game was so well suited to mixed doubles, Murray said: "I think my serve and the skills I have at the net lends itself to mixed doubles".
She'll go for No. 25 in women's doubles on Sunday - with Chan's sister as her partner. At the time, she denied taking the drug but did not appeal the ruling.
Says Keys: "She can buy me drinks, all of the drinks".
"It's been a lot of fun for me and a great opportunity for me to compete with Martina".
At the 2014 Wimbledon Championships, Chan for the first time reached the finals of the mixed doubles competition with Max Mirnyi to reach her first ever Grand Slam final.
Both are playing the best tennis of their careers after having surgery.