Hewitt, who is retiring after the Australian Open next year, will be forever remembered for his irrepressible fighting spirit and the 2002 champion typically saved three match points to extend an incredible final set on Court 2.
Nieminen, however, also making his last appearance at SW19, held his nerve to seal a 3-6 6-3 4-6 6-0 11-9 victory and book a second-round match-up with defending champion Novak Djokovic.
Hewitt twice led the Fin after winning the first and third sets but the Australian called two medical time-outs in the decider and finally, after exactly four hours on court, his resistance crumbled.
It means Hewitt has won 41 matches and lost 16 in his 17 appearances at the All England Club, and he arguably saved his most dramatic contest until last.
Only against David Nalbandian at the 2005 Australian Open, whom he beat 10-8 in the fifth set, has Hewitt played a longer decider and the 34-year-old was spurred on throughout by his famous Australian band of supporters.
After the match, Hewitt directed an emotional salute towards his loyal fan club and applauded all sides of the court, before making his exit.
Hewitt will return to the grass for one last time in the doubles event, where he plays alongside compatriot Thanasi Kokkinakis, but it is Nieminen who is now tasked with overcoming Djokovic, who beat Philipp Kohlschreiber earlier on Monday.
Nieminen was drawn against the world number one in the opening round of the French Open last month and he was beaten in straight sets.
The 33-year-old has tasted victory against Djokovic only once in their six previous meetings.