The Ligue 1 team had already progressed to the knockout stage but a win for Guimaraes and defeat for Real Betis would have seen the Portuguese side through from Group I.
Things looked good when the hosts took an 11th-minute lead through Rafael Crivellaro but two second-half minutes turned the game on its head.
Bafetimbi Gomis scored from the spot in the 63rd minute for a foul which earned home defender Guerreiro Pedro Correia a second yellow card.
Just two minutes later and Lyon were ahead when Jordan Ferri sent home a low shot as Lyon qualified as group winners along with Betis who drew 0-0 at home to Rijeka.
Andre Marco Matias fired wide from distance for the hosts but it was not long before they took the lead when Crivellaro slotted into the bottom left-hand corner of the goal from the centre of the penalty area.
Arnold Mvuemba missed the target in what was a good chance for the Lyon midfielder and Gael Danic had a shot on goal which was saved by home goalkeeper Renato Douglas.
The hosts then created a good opportunity only for Crivellaro to have his shot blocked.
Gomis and Mehdi Zeffane both had efforts for Lyon shortly after half-time, the latter especially a good opportunity but Douglas refused to be beaten.
Chris Malonga's shot was blocked for Guimaraes but Zeffane came within inches for Lyon when his effort hit the woodwork but the visitors were level moments later from the spot.
Guerreiro Pedro Correia fouled Yoann Gourcuff in the area with the defender sent off following a second yellow card.
Gomis then placed the ball high into the centre of the goal as the hosts' job became doubly difficult.
Within two minutes the game was turned on its head when Lyon doubled their lead.
Danic's ball from the left found Ferri in the centre of the area and he placed a low shot into the middle of the goal to put the group leaders ahead.
Andre Andre was thwarted by Lyon keeper Anthony Lopes before the hosts came within inches of equalising only for the woodwork to deny Nii Plange.
Guimaraes kept attacking and were again denied by the woodwork, this time Leandro Freire the man thwarted.