Last season's runners-up, who saw star striker Radamel Falcao leave for Manchester United on loan on transfer deadline day, came into the fixture having picked up just four points from their opening four fixtures under new coach Leonardo Jardim.
The league table made bleaker reading for Lyon, who had suffered three defeats after opening with a win, but it was the home side who took the lead through Nabil Fekir on the half-hour mark at Stade de Gerland.
Lucas Ocampos pulled the visitors level six minutes before the interval, but Corentin Tolisso's strike in the 73rd minute sealed the three points for Lyon, for whom goalkeeper Anthony Lopes made a number of crucial saves.
Fekir opened the scoring when he beat the offside trap to latch onto the end of a Steed Malbranque pass before drilling a low effort beyond goalkeeper Danijel Subasic.
However, that lead only lasted nine minutes.
Geoffrey Kondogbia did well to win back possession deep inside the Lyon half and squared to Ocampos, who sent an effort to the left of the goalkeeper and into the back of the net from 18 yards.
Monaco were unable to build on their leveller and Tolisso sparked jubilant scenes among the home supporters when he side-footed home from a Samuel Umtiti pull-back.
The visitors sent stopper Subasic forward for a late free-kick, but it was to no avail as Lyon clung on for the win.