It was the end of an era for Lleyton Hewitt, as the 2002 winner bowed out to Finland's Jarkko Nieminen 3-6 6-3 4-6 6-0 11-9.
Like Hewitt, Nieminen's retirement from the game is also on the horizon, but the world number 92 wildcard extended his time in SW19, with a second-round meeting against Djokovic on the cards.
Nick Kyrgios made life difficult for himself in his convincing victory over Diego Schwartzman.
Kyrgios was overheard shouting "dirty scum" during a contentious baseline call, although he later claimed the outburst was aimed at himself and not the umpire.
Fellow Australian Bernard Tomic was a five-set winner over Jan-Lennard Struff, while last year's quarter-finalist Marin Cilic overcame Japan's Hiroki Moriya 6-3 6-2 7-6 (7-4).
Novak Djokovic and Stanislas Wawrinka both negotiated their Wimbledon openers without too much trouble on Monday, progressing in straight sets.
Defending champion Djokovic was a 6-4 6-4 6-4 winner over Germany's Philipp Kohlschreiber before French Open champion Wawrinka progressed past Joao Sousa in the opening round for the second successive year.
While Djokovic was made to sweat on his first competitive grass-court outing, Sousa eventually reeled in Wawrinka before the Swiss blew him away in the third-set tie-break.
British number six Liam Broady gave home fans something to cheer as he fought back from two sets down to claim victory on his grand slam debut.
The 21-year-old edged out Marinko Matosevic 5-7 4-6 6-3 6-2 6-3.
Experienced campaigner Tommy Robredo mirrored his first-round exit at the Australian Open with defeat to John Millman, while Richard Gasquet and Grigor Dimitrov got past Luke Saville and Federico Delbonis respectively in straight sets.
Argentine pair Juan Monaco and Leonardo Mayer ousted Florian Mayer and Thanasi Kokkinakis respectively, although Horacio Zeballos fell 7-6 (7-4) 6-1 6-1 to David Goffin.
Denis Kudla came from two sets down to knock Pablo Cuevas out, Alexander Zverev edged his five-set thriller with Teymuraz Gabashvili, Marcos Baghdatis beat Donald Young and there were also wins for Marsel Ilhan and Milos Raonic.
Martin Klizan took Fernando Verdasco to five sets while French Open quarter-finalist Kei Nishikori was also made to sweat in his five-set victory against Italy's Simone Bolelli.
Santiago Giraldo awaits next - the Colombian suffering no such problems in his straight-sets success against Joao Souza.
Kenny de Schepper remains on course to repeat his fourth-round effort at Wimbledon two years ago after seeing off John-Patrick Smith in five sets, with fellow Frenchman Pierre-Hugues Herbert overcoming Hyeon Chung. Lucas Pouille was beaten in four sets by Kevin Anderson.
Earlier in the day, Ricardas Berankis progressed at 6-2 5-2 ahead thanks to Andreas Haider-Maurer's retirement, while there were also victories for Dominic Thiem, Marcel Granollers-Pujol and John Isner over Dudi Sela, Janko Tipsarevic and Go Soeda respectively.
Tommy Haas moved past Dusan Lajovic, Victor Estrella Burgos set up a second-round meeting with Wawrinka by beating Benjamin Becker while Matthew Ebden and Steve Johnson beat Blaz Rola and Lukas Lacko.