Aim: We performed a meta-analysis of S-1-containing regimens versus control in the management of locally advanced/metastatic non-small-cell lung cancer. Methodology: Eligible studies included randomized studies evaluating S-1-containing regimens in the settings of locally advanced, first-line metastatic or second-line metastatic non-small-cell lung cancer. Results: Pooled odds ratio for overall response rate was 1.09 (95% CI: 0.85–1.38; p = 0.2), the pooled hazard ratio for progression-free survival was 0.98 (95% CI: 0.88–1.09; p = 0.69) and the pooled hazard ratio for overall survival was 0.98 (95% CI: 0.88–1.10; p = 0.75) for S-1-based regimens versus control. Moreover, the relative risk of febrile neutropenia was 0.34 (95% CI: 0.20–0.59; p = 0.0001). Conclusion: Our meta-analysis has demonstrated that S-1-based regimens are associated with similar efficacy outcomes and better hematological tolerability.