The popular theory blaming the rapper for her loss circulated on social media with several users taking hits at him.
"Drake is the Jessica Simpson to Serena's Tony Romo" one user wrote on Twitter followed with the hashtag 'BlameDrake'.
"Drake jinxed Serena man," another user posted on the social media site.
The hip-hop mogul, who stood in the stands rooting Williams on, had even before Friday developed a reputation as bad luck for teams and athletes.
For example, Drake watched on as his favorite college team the Kentucky Wildcats, whose undefeated season ended in the semifinals of the NCAA Tournament against Wisconsin Badgers.
He has also been blamed for Cleveland Browns quarterback Johnny Manziel's 'lackluster' career, the Seattle Hawk's most recent Super Bowl loss and for LeBron James's cramps during his last year playing with the Heat, according to the Washington Post.
This is not his first time he has attended one her matches as he has been pictured previously during the Rogers Cup in 2011, but Williams won 4-6, 6-3, 6-3 against Zheng Jie.
After the match a heartbroken Serena was spotted leaving the stadium with her rumored boyfriend Drake, with the two getting into the same car and driven away from the facility.
Serena did not even change before leaving, seeming to want to get out as quickly as possible following her loss.
Vinci, who is unseeded, will now take on countrywoman Flavia Pennetta in the final on Saturday.
Pennetta upset Simona Halep - the number two seed - earlier in the day.
Serena seemed to be well on her way to the final after blasting past Vinci in the first set, but the Italian began rallying better in the second set, and by the final games of the third Serena appeared exhausted on the court.
By the time Vinci hit her final winner - a volley at the net - Serena appeared ready to leave.
She graciously shook her opponent's hand before immediately leaving the stadium, waving to the fans as she made her exit.
Serena appeared to be having problems with her ankle during the match and had the trainer tend to her at one point.
Serena, 33, had not lost in a major since Wimbledon in 2014 prior to her defeat on Friday, and had only lost two matches this season.
Serena kept things brief during her press conference following the match, saying; 'I don't want to talk about how disappointing this is for me. If you have any other questions I'm open to that.'
She did compliment Vinci's performance during the match.
I thought she played the best tennis in her career,' Williams said.
"You know, she's 33, and you know, she's going for it at a late age. So that's good for her to keep going for it and playing so well.
"Actually, I guess it's inspiring. But, yeah, I think she played literally out of her mind."
When asked about the pressure put on her by those hoping to see her win the Grand Slam, Serena said; 'I told you guys I don't feel pressure. I never felt pressure. I don't know. I never felt that pressure to win here. I said that from the beginning.'
The entire press conference lasted exactly three minutes.
Rumored boyfriend Drake cheered Serena on during the match from a private suite, and some are now jokingly blaming her loss on him.
Serena was aiming to become the first woman since Steffi Graff in 1988 to win all four majors in the same calendar year.
She was also aiming to match Graff's record of 22 Grand Slam singles titles, the most of any player in the Open Era.
Prior to Friday, she had never lost to Vinci, who at 32-years-old is just a year younger than Serena.
What's more, she had never even lost a set to Vinci, and defeated her in Toronto last month.
Vinci apologized to the crowd after her victory.,
"For the American people, for Serena, for the Grand Slam and everything,' she said.
"But today is my day. Sorry, guys.'"
She then added; 'It's an incredible moment for me. It's amazing. It's like a dream, you know? I'm in the final. I beat Serena. I think [it's] the best moment of my life.'
When asked later about how she managed to play so well, Vinci told reporters; 'In my mind, I say put the ball on the court. Don't think.
'Try to put all the ball on the court. Don't think about that Serena is in the other court. And run, you know, when you put the ball, run. Don't think and run. And then I won.'
Vinci used her trademark slice expertly in the final two sets, making it near impossible for Serena to generate any pace on the ball and forcing her to play Vinci's game.
She grew increasingly frustrated during the contest, receiving a code violation at one point for smashing her racket.
Vinci now becomes the lowest ranked played to reach the finals of the US Open since 1997 - when Serena's sister Venus took on Martina Hingis.
Serena played her sister in the quarterfinals here in another three set match, pulling out that victory 6 - 3 in the third.
Vinci and Pennetta - who used to be roommates - played each other in the quarterfinals of the 2013 US Open, with Pennetta winning in two sets.
Speaking with ESPN, Serena's mother Oracene Price - who seldom comments on her daughters - admitted that she appeared to be felling the pressure of the Grand Slam bid.
Her coach Patrick Mouratoglou added that she did not appear to be herself when he spoke to her earlier in the day.
Despite a high number of unforced errors - 40 to Vinci's 20 - Serena had a good day, hitting 50 winners and winning 93 points, more than her opponent who had 80 for the match.
She did suffer four breaks of serve, but also managed to break Vinci four times as well.
Serena also had four double faults, which were balanced out by her 16 aces.
