The study goal was to determine the effects of sodium propionate (NaPr) during the postpartum period on lactation performance, milk fatty acid (FA) profile, blood metabolites, and fat mobilization. This study selected 24 cows with the same parity (3), similar due date, and physical condition in the postpartum period and randomly allocated them into two groups. The constituents of the two treatments were (1) a normal diet for the Control group and (2) a normal diet containing 246 g d^–1 of NaPr for the NaPr group. This study demonstrated that supplementation of NaPr to dairy cows in the postpartum period had no significant impact on dry matter intake (DMI) and milk composition. The milk proportions of 4:0, 8:0, 10:0, 13:0, 16:0, cis-10 15:1, cis-13, cis-16 22:2, total odd-chain FA, and de novo FA increased, and those of all remaining individual saturated fatty acids (SFA) and preformed FA decreased in cows fed NaPr vs. the Control diet. Supplementing with NaPr significantly increased the concentrations of triglycerides (TG), glucose, and insulin in the plasma of cows. This indicates that NaPr supplementation in the postpartum period provides energy for cows, which is beneficial for the body’s glucose and lipid balance. The TG content, Perilipin-1 (PLIN1) protein expression, and orange-red lipid droplet deposition in adipose tissue were increased in cows fed NaPr vs. the Control diet. The mRNA expression of ACCα and ACSS2 in adipose tissue was up-regulated, and the expression of CPT1A and CPT2 genes was down-regulated. This indicates that dietary NaPr supplementation promotes the generation of acetyl CoA, thereby up-regulating the FA synthesis pathway and reducing FA oxidation. In conclusion, dietary supplementation with NaPr promotes energy deposition, improves milk quality and fat accumulation, and alleviates negative energy balance (NEB) in postpartum dairy cattle.