The Belgian will retire for the second time after the US Open later this month and will do so without an Olympic medal after her first and last Games was brought to an end.
Sharapova made a fast start and, although Clijsters delighted the Centre Court crowd by breaking back in the second set, she could not force a decider and lost out 6-2 7-5.
Clijsters was happy to exit centre stage, saying: 'It was great. It's a nice experience every time you go out on Centre Court so I'm happy to say that my last match at Wimbledon was on Centre Court.
'I think overall she was the better player. She served well and I think of all the matches that I've played against her this is the best that she's served, and on grass it's going to be tough to beat her.'
Sharapova was thrilled with the result, and she said: 'I certainly had to step up today from my previous round. Kim is so experienced, a grand slam champion.
'I knew that it would be really tough and I really wanted to win today so I stayed extra focused. It was obviously getting close and it was such a tight second set I was just happy to get through this one.'
Russia is now guaranteed at least a silver medal in the women's Singles because in the last four Sharapova will face countrywoman Maria Kirilenko.
The 14th seed earlier pulled off a very impressive 7-6 (7/3) 6-3 victory over sixth seed and former Wimbledon champion Petra Kvitova.
Serena Williams advanced with a 6-0 6-3 win over eighth seed Caroline Wozniacki.
The USA player is likely to have a tougher time tomorrow against Victoria Azarenka, whom she edged out in two tight sets on her way to a fifth Wimbledon title four weeks ago.
Azarenka was forced to dig deep by seventh seed and Wimbledon semi-finalist Angelique Kerber from Germany before coming through 6-4 7-5.
Williams is still on track for two gold medals after teaming up with sister Venus to defeat French Open champions Sara Errani and Roberta Vinci from Italy 6-1 6-1 in the quarter-finals of the women's Doubles.
Kirilenko is also still in both events and will be the next opponent for the Williams sisters along with partner Nadia Petrova, while the other semi-final will see USA top seeds Liezel Huber and Lisa Raymond meet Czechs Lucie Hradecka and Andrea Hlavackova.