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Anti‐programmed cell death 1 (anti‐PD‐1) therapy shows definite but modest activity in patients with advanced/metastatic head and neck squamous cell carcinoma (HNSCC). Preliminary evidence suggests that SN‐38, an activated form of irinotecan that increases expression of the transcription factor FoxO3a, can suppress programmed cell death ligand‐1 (PD‐L1) expression in breast and ovarian tumor models. We analyzed the SN‐38‐mediated activation of natural killer cells in vitro and explored the efficacy of SN‐38 in combination with anti‐PD‐1 for treatment in vivo. In vitro, SN‐38 enhanced the expression of FoxO3a and reduced the expression of c‐Myc and PD‐L1 dose‐dependently in tumor cells. Low‐dose SN‐38 increased interferon‐γ secretion by NK cells and promoted NK cell‐mediated cytotoxicity in tumor cells. In vivo studies revealed that at non‐cytotoxic drug concentrations, SN‐38 significantly enhanced anti‐PD‐1 activity in suppressing murine tumor growth. We found increased NK cell and CD8+ T‐cell infiltration in post‐treatment tumors. RNA‐seq analysis indicated that SN‐38 increased the enrichment of immune cells and biological function genes related to the immune responses. SN‐38 is a potentially beneficial adjunct to checkpoint inhibitor therapy in HNSCC. Further studies exploring its mechanism of action and possible applications are necessary. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]