Federer's bid to win a ninth Wimbledon title came to an astonishing end as the defending champion collapsed to Kevin Anderson in a nail-biting four hour and 13-minute classic.
It was Federer's earliest departure from Wimbledon since his shock second round defeat against Sergiy Stakhovsky in 2013.
Gael Monfils tamed the power of American Sam Querrey to reach the Wimbledon fourth round for the first time on Friday.
The big South African Anderson, ranked at eight in the world, reached the Wimbledon last 16 on Friday for the fourth time.
Rafael Nadal's surprise quarter-final exit at the Madrid Masters has seen the Spaniard replaced as world number one by Roger Federer.
Ranked a humble 89, Simon landed without his coach and other support staff but was ready for the two Grand Slam finalists in 2017 at the Tata Open.
Simon, who was once a top-10 player but now placed a humble 89th, shrugged off opening set debacle to stun Cilic, the 2017 Wimbledon finalist, in one hour and 51 minutes.
Top seed Cilic from Croatia outplayed eighth seed Frenchman Pierre-Hugues Herbert 6-3 6-2 in 64 minutes while Anderson survived a mighty scare from a dogged Mikhail Kukushkin.
The big-serving 31-year-old Kevin Anderson fell to the top-ranked Rafael Nadal 6-3, 6-3, 6-4 at Arthur Ashe Stadium.
Rafael Nadal won his 16th Grand Slam title and third US Open crown by defeating South African 28th seed Kevin Anderson.
The Spanish tennis superstar overwhelmed Kevin Anderson 6-3, 6-3, 6-4 on Sunday to win his third championship at Flushing Meadows.
Kevin Anderson's joy and enthusiasm were evident after his impressive 4-6, 7-5, 6-3, 6-4 win over Pablo Carreno Busta.
Cliff Drysdale was the last South African man in the US final in 1965 but he was defeated by Manuel Santana.
South African Kevin Anderson has reached a first Grand Slam semi-final at the 34th attempt and is in no mood to stop now.
Football, rugby and cricket dominate the sport scene in the republic, taking most of the sponsorship money and the media space.