Streptococcus suis, an emerging zoonotic pathogen, causes invasive infections and substantial economic losses in the pig industry worldwide. Antimicrobial resistance against 22 antibiotics was studied for 200 S . suis strains collected in different geographical regions of France. Most of the strains (86%) showed resistance to at least one antibiotic with a low rate of resistance to fluoroquinolones, penicillins, pleuromutilin, and diaminopyrimidine-sulfonamides, and a higher rate to macrolides-lincosamides and tetracycline. Multi-resistance patterns were observed in 138 strains; three of them being resistant to six antibiotic families. Statistical analyses highlighted a decrease in the resistance to trimethoprim-sulfamethoxazole, in our collection, between the two periods studied—before 2010 and after 2015—as well as an impact of the geographical origin with a higher rate of resistance to macrolides-lincosamides and penicillin in Brittany than in the other French regions. Furthermore, macrolides-lincosamides and tetracycline resistance patterns were more likely to be found in pig isolates than in human and wild boar isolates. A difference in resistance was also observed between serotypes. Most of the penicillin-resistant strains belong to serotypes 1, 5, 9, 11, 12, 15, 27, and 29. Finally, penicillin and pleuromutilin resistances were mostly found in “non-clinical” isolates. The empirical treatment of human and porcine infections due to S. suis in France can therefore still be carried out with beta-lactams. However, this study emphasizes the need to monitor antimicrobial resistance in this zoonotic pathogen.