The N-methyl-D-aspartate receptor (NMDAR) plays a key role in the pathophysiology of depression. Serine racemase (SRR, encoded by Srr) converts L-serine to D-serine, an endogenous co-agonist at the glycine site of the NMDAR. Knock-out (KO) of Srr did not alter behavioral signs of depression compared with wild-type (WT) mice as evaluated by locomotion, tail suspension, forced swimming, and 1% sucrose preference tests. However, chronic social defeat stress (CSDS: 10 days) caused a depression-like phenotype as measured by these same tests in WT mice but not in Srr KO mice, suggesting that decreased D-serine co-agonist activity confers resilience against CSDS. In WT mice, CSDS decreased brain-derived neurotrophic factor (BDNF) expression and phosphorylation/activation of its receptor TrkB in prefrontal cortex (PFC), dentate gyrus (DG), and the CA3 region of the hippocampus, but increased BDNF and phosphorylated TrkB in the nucleus accumbens (NAc). Conversely, CSDS did not alter BDNF or TrkB phosphorylation in any brain region of Srr KO mice. Administration of D-serine through drinking water (600 mg/L for 20 days) 10 days prior to and during CSDS restored the depression-like phenotype in Srr KO mice. These findings suggest that reducing brain D-serine may improve stress resilience, thereby reducing depression risk.