Young midfielder Corentin Tolisso's winner saw Lyon inflict Monaco's third defeat of the fledgling Ligue 1 season.
Nabil Fekir's opener was quickly cancelled out by Lucas Ocampos and Monaco, led by Dimitar Berbatov, threatened repeatedly -- but Tolisso struck in the 74th minute to secure a 2-1 win, only the second in five games this season for Hubert Fournier's side.
Monaco were second in the table last season, their first following promotion back to the top flight, but having lost the likes of James Rodriguez and Radamel Falcao this summer they have struggled to reproduce that form.
They had the first chance of Friday night's game when Yannick Ferreira Carrasco went past Samuel Umtiti and fired the ball goalwards, but Christophe Jallet raced back to clear the ball off the line.
Lyon were also denied by a clearance from a defender shortly afterwards, Layvin Kurzawa denying Steed Malbranque.
Anthony Lopes made a superb full-length diving save to keep out Ferreira Carrasco's header from Dimitar Berbatov's cross, but Monaco's lively start was to count for nothing.
Alexandre Lacazette, fresh from signing a new two-year contract extension with Lyon, created the opening goal as he burst down the right and exchanged passes with Malbranque before teeing up Fekir to shoot left-footed past goalkeeper Danijel Subasic.
But the lead lasted only eight minutes before Geoffrey Kondogbia dispossessed the struggling Umtiti and surged forward before laying the ball off to the unmarked Ocampos, who curled home right footed.
It was 1-1 at half-time and Lopes tipped behind Berbatov's goalbound header early in the second period before Lacazette's volley was saved at the other end.
Berbatov threatened twice more, with a 20-yard effort and another header, but Lopes was equal to the task on each occasion.
But for all the visitors' pressure, they were to leave empty-handed. Umtiti had endured a shaky evening defensively but showed his overlapping ability by haring down the left flank and cutting the ball back to Tolisso, who found the net with a low drive from 12 yards.