Abstract Background This phase II trial was designed to evaluate the efficacy and safety of S‐1 combined with weekly irinotecan as a second‐ or third‐line treatment for patients with advanced or recurrent squamous cell lung cancer. Methods Patients with a body surface area <1.25, 1.25–1.50, and >1.50 m 2 received oral S‐1 on days 1–14 at 80, 100, and 120 mg/day, respectively, and irinotecan on days 1 and 8 at 70 mg/m 2 every 3 weeks. The primary endpoint was the overall response rate, and the secondary endpoints were progression‐free survival, overall survival, and the incidence and severity of adverse effects. Results Between September 2011 and December 2014, 30 patients were enrolled in this study. The overall response rate was 6.7% (95% confidence interval CI: 0.8%–22.1%), and the disease control rate was 73.3%. The median progression‐free survival was 3.0 months (95% CI: 2.5–3.4 months), and the median overall survival was 10.5 months (95% CI: 5.6–13.7 months). Grade 3/4 treatment‐related adverse events were reported in ≥10% of the patients, including leukopenia (21%), neutropenia (21%), anemia (17%), anorexia (10%), and hypokalemia (10%). Conclusions Although the treatment‐related adverse events were manageable, the combination of weekly irinotecan and S‐1 did not have the expected effect.