7 biggest US Open upsets since 2000 ft. Serena Williams losing Calendar Slam, 5-time defending champion Roger Federer losing to Juan Martin del Potro

Serena Williams and Roger Federer have both been involved in some of the biggest upsets of the US Open since 2000. The defeats robbed both tennis greats of scripting some major records.

The New York Major is around the corner, with Novak Djokovic and Coco Gauff being the defending champions. The Serb will aim to win a record 25th Grand Slam title but he is bound to face a tough challenge from the likes of Carlos Alcaraz, Jannik Sinner and Daniil Medvedev, among others.

In the women's tournament, Gauff is set to have a tough title defense, as her form hasn't been at its best and the likes of Iga Swiatek, Aryna Sabalenka and Jessica Pegula are capable of going all the way.

The tournament has seen some exciting encounters this century and there have also been a number of instances when heavily-favored players bowed out against unheralded opponents. On that note, let us take a look at the seven biggest upsets from the US Open since 2000.

#7 John Millman def. Roger Federer at US Open 2018

Roger Federer entered the 2018 edition of the US Open after reaching the final of that year's Cincinnati Open. The Swiss was seeded second in the tournament and booked his place in the fourth round after straight-set wins over Yoshihito Nishioka, Benoit Paire and 30th seed Nick Kyrgios,

Here, Federer faced John Millman and started well by taking the first set 6-3. However, the Aussie bounced back to win the next three sets 7-5, 7-6(7), 7-6(3) to reach his maiden Grand Slam quarterfinal, where he lost to eventual champion Novak Djokovic.

This remains Millman's only win over Federer, as the Swiss leads 3-1 in the head-to-head between the two.

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#6 Marin Cilic def. Roger Federer at US Open 2014

Roger Federer entered the 2014 US Open after impressive runs at the Canadian Open and the Cincinnati Open. The Swiss was the runner-up in Toronto while he was triumphant in Cincinnati.

Federer reached the semifinals after defeating Marinko Matosevic, Sam Groth, Marcel Granollers, Roberto Bautista Agut and Gael Monfils. Here, he took on 14th seed Marin Cilic, against whom, he had a 5-0 head-to-head record at the time.

However, the Croat produced a fine performance to register a 6-3, 6-4, 6-4 win and reach his maiden Grand Slam final. Cilic eventually went on to win the 2014 US Open by beating Kei Nishikori in the title clash.

The Croat never won another match against Roger Federer.

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#5 Sloane Stephens def. Venus Williams at US Open 2017

Sloane Stephens' run at the 2017 US Open is nothing short of a fairytale. The then-World No. 83 entered the tournament using a protected ranking and reached her second Grand Slam semifinal after defeating Roberta Vinci, 11th seed Dominika Cibulkova, Ashley Barty, 30th seed Julia Gorges and 16th seed Anastasia Sevastova.

Here, she faced ninth seed Venus Williams, who was the highest-ranked player left in the tournament at the time. Stephens started the match by winning the first set 6-1. However, Williams bounced back brilliantly by dominating the second set and winning it 6-0 to force the match into a decider.

The third set was a close affair and Stephens managed to win it 7-5 to reach her maiden Grand Slam final. Here, she thrashed her compatriot Madison Keys to become the lowest-ranked US Open champion ever.

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#4 Samantha Stosur def. Serena Williams at US Open 2011 final

Serena Williams and Samantha Stosur's respective runs to the 2011 US Open final were contrasting, with the American winning all of her matches in straight sets while the Aussie had to grind out a few tough wins.

While Stosur was the higher-ranked player, Williams was in sublime touch and beat her before in the final of the Canadian Open. The Aussie produced a stellar performance to win her only Grand Slam singles title. She remains the last player from her nation to win the New York Major.

This was also Williams' first defeat in a Grand Slam final since Wimbledon 2008.

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#3 Juan Martin del Potro def. Roger Federer at US Open 2009 final

Roger Federer won a then-record 15th Grand Slam title at the 2009 Wimbledon Championships by defeating Andy Roddick in the final. The Swiss then reached the quarterfinals of the Canadian Open before winning his fourth title in Cincinnati.

Federer entered the US Open as the top seed and five-time defending champion. He reached the final after securing wins over Devin Britton, Simon Greul, 31st seed Lleyton Hewitt, 14th seed Tommy Robredo, 12th seed Robin Soderling and fourth seed Novak Djokovic. This marked the third season when the Swiss reached all Grand Slam finals.

Federer faced sixth seed Juan Martin del Potro in the title clash, with their head-to-head being 6-0 in the former's favor at the moment. The Swiss started the match well by taking the opening set 6-3 before the Argentine leveled things up by winning the second via a tiebreak. The then-World No. 1 then restored his lead by taking the third set 6-4 but Del Potro once again bounced back to take the match into a fifth set.

The Argentine put on a dominant display in the last set to register a 3-6, 7-6(6), 4-6, 7-6(4), 6-2 to win his first and only Grand Slam title.

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#2 Arnaud Clement def. Andre Agassi at US Open 2000

Andre Agassi entered the 2000 edition of the New York Major as the World No. 1 and the defending champion. The American started the tournament strongly with a comprehensive 6-4, 6-2, 6-0 win over compatriot Alex Kim.

Here, Agassi faced Arnaud Clement, whom he beat in both of their prior encounters. However, the Frenchman dominated their clash and won 6-3, 6-2, 6-4 to eliminate Agassi. He eventually went on to reach the quarterfinals of the tournament before losing to Lleyton Hewitt.

Agassi, however, did his next Grand Slam clash against Clement to win the 2001 Australian Open.

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#1 Roberta Vinci def. Serena Williams at US Open 2015

Serena Williams was at her dominant best during the 2015 season, winning the Australian Open, French Open, and Wimbledon, and was on course to become the first player to win the Calendar Slam since Steffi Graf. The American entered that year's US Open after winning the Cincinnati Open.

She reached the semifinals of the tournament while dropping just one set, defeating Vitalia Diatchenko, Kiki Bertens, Bethanie Mattek-Sands, Madison Keys and Venus Williams.

Here, she faced then-World No. 43 Roberta Vinci and took the lead in the match by taking the first set 6-2. However, the Italian produced a spectacular comeback to win the next two sets 6-4, 6-4, ending Williams' hopes of a Calendar Slam and reaching her maiden Grand Slam final.