Background: This study investigated the efficacy of first-generation cephalosporin (cefazolin) and third-generation cephalosporin (ceftizoxime) as prophylactic antibiotics in patients undergoing percutaneous nephrolithotomy (PCNL) surgery. Objectives: The study also examined the incidence of postoperative complications, hospitalization duration, and time to return to normal life. Methods: This prospective cross-sectional study included patients (≥ 20 years) who underwent PCNL surgery at Razi, Golsar, and Pars Hospitals from January 1, 2013, to December 31, 2022. Patients were divided into two groups, receiving 1 mg/kg of either first-generation (cefazolin) or third-generation (ceftizoxime) cephalosporin intravenously, 30 minutes before surgery. The incidence of postoperative complications, hospitalization duration, and return to normal life were compared based on the type of prophylactic antibiotic. Risk factors were evaluated using chi-squared tests followed by multivariate logistic regression analysis. Results: The ceftizoxime group showed significantly lower rates of overall complications (13.0% vs. 31.4%) and postoperative fever (2.8% vs. 15.0%) compared to the cefazolin group. The ceftizoxime group also had a significantly shorter hospitalization duration (1.31 ± 1.18 days) compared to the cefazolin group (4.03 ± 1.57 days) (P = 0.000). Additionally, the ceftizoxime group had a significantly faster return to normal life (5.97 ± 3.37 days) compared to the cefazolin group (8.15 ± 2.93 days) (P = 0.001). Conclusions: The third-generation prophylactic cephalosporin (ceftizoxime) was more effective than the first-generation (cefazolin) in reducing postoperative fever rates, shortening hospitalization duration, and expediting the return to normal life for patients.