Background and Objectives: Postoperative fatigue (POF) is a frequent complication that negatively affects recovery and quality of life following surgery. Ketamine and esketamine, as N-methyl-D-aspartate (NMDA) receptor antagonists, may reduce postoperative fatigue; however, current evidence remains inconclusive. This systematic review and meta-analysis aimed to evaluate the effects of perioperative ketamine and esketamine on postoperative fatigue in adult surgical patients. Materials and Methods: A systematic search of major electronic databases was conducted to identify randomized controlled trials comparing perioperative ketamine or esketamine with placebo or standard care in adult surgical patients. Fatigue outcomes during the first postoperative week were analyzed using random-effects meta-analyses and reported as standardized mean differences (SMDs) with 95% confidence intervals (CIs). Subgroup analyses were performed according to NMDA antagonist type, surgical procedure, and administration regimen. Sensitivity analyses included exclusion of studies using patient-controlled intravenous analgesia (PCIA) and leave-one-out analyses. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool, and certainty of evidence was evaluated using the GRADE approach. Results: Eight randomized controlled trials (n = 906 participants) were included in the qualitative and quantitative synthesis. No significant overall reduction in postoperative fatigue was observed at POD1 (SMD −0.37, 95% CI −0.87 to 0.13), although esketamine demonstrated a significant benefit in subgroup analysis. Ketamine/esketamine significantly reduced postoperative fatigue at POD3 (SMD −0.58, 95% CI −0.86 to −0.30) and POD7 (SMD −0.38, 95% CI −0.65 to −0.12). Subgroup analyses demonstrated greater reductions in fatigue among patients undergoing colorectal surgery. Sensitivity analyses excluding PCIA studies and leave-one-out analyses confirmed the robustness of the findings at POD3 and POD7. The certainty of evidence was rated as low for POD1 and moderate for POD3 and POD7. Conclusions: Perioperative ketamine and esketamine were associated with reduced postoperative fatigue from POD3 onward in adult surgical patients, with more consistent benefits observed in colorectal surgery populations. Further high-quality studies are needed to determine the clinical significance of these findings and their impact on postoperative recovery outcomes.