The second-seeded Czech, who has not played since the WTA tournament in Doha in February due to an elbow injury, had a tough match in Paris.
She had no less than 45 unprovoked mistakes against the 97-ranked Frenchwoman.
This is only the third time a reigning champion has gone straight out in the French Open women's singles.
The two previous ones who did it were Anastasia Myskina in 2005 and Jelena Ostapenko in 2018.