Lyon was in cruise control with a 3-0 lead courtesy of goals from Lucas Paqueta in the ninth minute, Houssem Aouar after 28 minutes and a penalty from Memphis Depay just before the half-time break.
However, the home side fought back with second-half goals from Brendan Chardonnet in the 52nd minute and Irvin Cardona 20 minutes later.
Mid-table Brest matched Lyon in the early stages as Rudi Garcia's men looked to bounce back from their defeat to Montpellier last weekend.
But Brest goalkeeper Sebastien Cibois, only playing his fourth senior game for the club, handed Lyon the opening goal.
The 22-year-old fluffed a clearance which allowed Brazilian midfielder Paqueta to walk the ball into an empty net.
Brest's Paul Lasne was then caught in possession by Thiago Mendes who found Depay. The Netherlands attacker in turn set up Aouar to score.
Cibois, who started his career at PSG, was at fault again for the third goal when he chopped down Depay who then stepped up to put away the penalty.
To its credit, Brest hit back with two goals in the second period but was unable to repeat their performance from December's first meeting when it scored in the third minute of stoppage-time to secure a 2-2 draw.
Lyon leads the way on goal difference from Lille, with champion Paris Saint-Germain a point further back in third.
Lille is at Lorient on Monday (AEDT) while PSG hosts Monaco in a game where Kylian Mbappe faces his former club