Paes and Sania lost 5-7 6-7(5) to the top seeded pair of Max Mirnyi and Victoria Azarenka from Belarus in the last-eight stage match, which was spread over two days due to bad light.
The Indians were trailing 2-3 in the second set, when play was stopped on Aug 3. Paes and Sania did fight bravely but the failure to cash in on the break points dented their chances.
Out of eight chances in the second set, they could convert only one. Nevertheless, they fought hard and stretched the second set to a tie-breaker, which itself was a tight affair.
But it was not meant to be the Indians' day. Mixed doubles event was considered India's best medal bet as the draw was of 16 pairs and a team needed to win three matches to win a bronze.
The defeat means Sania's career may end without an Olympic medal as the injury-ravaged Indian may not play in the next Games in Brazil.
Paes, thus, remains the only tennis player from the country to win an Olympic medal -- bronze at the 1996 Atlanta Games in the men's singles.
The build-up to the Olympics was marred with a selection row as players resorted to bickering. Both Mahesh Bhupathi and Rohan Bopanna refused to play with Paes and insisted on being paired together.
However, they could not go beyond the second round. Paes and Vishu Vardhan also bowed out after a second round defeat, though the pair fought valiantly against tough opponents.