Purpose <p>This study examined how optimism and sense of coherence mediated the relationships between gratitude and psychological distress among cancer patients in China.</p> Methods <p>This cross-sectional study was conducted between September 2023 and June 2024. A total of 215 cancer patients undergoing radiotherapy completed questionnaires assessing sociodemographic variables, disease-related factors, gratitude, optimism, sense of coherence, and psychological distress. A chain mediation model was tested using the PROCESS macro in SPSS to examine the chain mediating roles of optimism and sense of coherence in the relationship between gratitude and psychological distress.</p> Results <p>Psychological distress was negatively correlated with gratitude, optimism, and sense of coherence. Gratitude had a negative effect on psychological distress through three distinct pathways: the mediating effect of optimism (effect =  − 0.017), the mediating effect of sense of coherence (effect =  − 0.015), and the chain mediating effect of optimism and sense of coherence (effect =  − 0.008), accounting for 17%, 15%, and 8% of the total effect, respectively.</p> Conclusions <p>Gratitude influences psychological distress in cancer patients both directly and indirectly through optimism and sense of coherence. The improvement of psychological distress should not be limited to symptom relief, but should also focus on enhancing patients’&#xa0;positive emotional experiences and fostering positive psychological resources to improve psychological distress.</p>