(1) Background: Postoperative antibiotic prophylaxis in dogs undergoing tibial plateau leveling osteotomy (TPLO) is controversial. We evaluated the effect of perioperative antibiotic administration on the incidence of surgical site infection (SSI) and bone healing in dogs that underwent TPLO procedures and compared this protocol with cases that received prolonged postoperative antibiotic treatment. (2) Methods: Two different antibiotic treatment protocols were used. In group A, cefazolin (22 mg/kg IV) was administered preoperatively 30–60 min before skin incision and repeated every 90–120 min intraoperatively. Antimicrobial prophylaxis was extended in the postoperative period with oral cefazolin (22 mg/kg BID) for 10 days after surgery. In group B, dogs only received perioperative treatment, at the same dose used in group A. Dogs were considered to have SSI in cases of incisional drainage, wound dehiscence, positive bacterial culture, or evidence of radiographic signs of infection. (3) Results: In group A, SSI was observed in 3/61 TPLOs (4.9%). In group B, SSI was present in 3/51 TPLOs (5.9%). There was no difference between the two groups. (4) Conclusions: Our results indicate that perioperative antibiotic prophylaxis in TPLO procedures is sufficient to maintain overall low rates of SSI. The incidence of SSI was similarly low compared to the rate observed in dogs that also received postoperative antibiotic treatment.