The American was also contesting a second grand slam final in the same season for the first time since 2003 after finishing runner-up to Serena at the Australian Open.
Both players went on court without winning a title this year.
"Thanks to my team who have been here day in and day out".
After an initial decade of dominance, Williams has not had the kind of success she had when she started her tennis career. She won 7-6, 6-0. The women's final will feature #Venus Williams and Gabrine Muguruza, while the men's final will see #Rodger Federer go against Marin Cilic.
The 23-year-old Muguruza stormed into the final by beating Magdalena Rybarikova, Thursday. I was doing everything I could to be prepared. In particular, Williams had the momentum in a long rally on that first set point, but lost it with a netted forehand. "It's really good to have a good group of juniors pushing each other". She'll have another chance of becoming the oldest women's Grand Slam champion in the Open Era at the US Open. "It should be the biggest story ever if Venus wins this", 1999 Wimbledon winner Lindsay Davenport told the Orlando Sentinel.
"I miss you", she said. Williams won the ladies singles crown in 2000, 2001, 2005, 2007 and 2008.
"Roger", Muguruza said with a smile and giggle. So there's definitely something for me to learn from this. "I'm looking forward to the rest of the summer".
Muguruza beamed as she lifted the trophy above her head, posing for photographs before parading along with Williams around the court to huge applause. "She knows how to prepare, how to train, what to do". It won't be a given but I'll give it my all.
On her way to the final, Muguruza took down top seed Angelique Kerber and seventh seed Svetlana Kuznetsova. She is one point away from the winning the set.
Muguruza, who has a Venezuelan mother and a Spanish father but eventually opted to represent Spain after the family moved to Europe when she was six, has won only three titles in her life, though the world No 15 is clearly a player for the big occasion. For a player whose services had carried her throughout the tournament, it was a bad situation for her to be in.
"Well, I think I'm here because I've done a hard work before".