Moussa Maazou, who was later sent off, gave the Portuguese visitors a first-half lead that was wiped out by Maxime Gonalons after the interval.
Although both teams have struggled for consistency in their respective domestic leagues, Guimaraes began their European campaign with a resounding 4-0 win over Rijeka while Lyon claimed a creditable goalless draw at Real Betis.
And it was Les Gones who threatened first at home, a right-footed strike from Alexandre Lacazette flying past the right post.
Guimaraes replied with an effort from Chris Malonga Ntsayi which was also wide of the mark, but the Portuguese club soon began to show their skills and Maazou came close with a curling shot which came within touching distance.
Abdoulaye Ba also put a header wide as the visitors continued to press, and they were rewarded after 39 minutes when Maazou smashed Andre Marco Matias' cross high into the net.
Lyon showed greater purpose after the interval and the scores were level in the 54th minute thanks to Gonalons, who met a free-kick from Arnold Mvuemba to head home from the centre of the area.
The home side were now the dominant force and Gueida Fofana should have done better with a close-ranger header after 65 minutes which the midfielder instead directed over.
Guimaraes goalkeeper Douglas was put to the test seven minutes from time, tipping Bafetimbi Gomis' vicious left-footed strike around the post.
And the Brazilian ensured the scores would stay level with a stoppage-time save from Gomis' teasing volley, moments before Maazou saw a second yellow card for his clumsy challenge on Clement Grenier in the last action of the match.