BACKGROUND: Compared with face-to-face mindfulness-based interventions (MBIs), online mindfulness interventions may be more convenient for patients with limited resources and can provide self-help mindfulness methods to improve the quality of life of cancer patients. This study investigated the effects of guided self-help mindfulness-based interventions (GSH-MBIs) on psychological distress, quality of life and sleep quality in patients with hepatocellular carcinoma and explored the underlying mechanisms. METHODS: A total of 122 patients with hepatocellular carcinoma were randomly divided into the intervention group or the conventional treatment group. Psychological distress, quality of life, sleep quality, psychological flexibility and perceived stress were evaluated in the groups before the intervention at baseline, after the intervention, at 1-month follow-up and 3-month follow-up. The intervention's effects over time and the potential mediating effects were analysed using generalized estimating equations (GEE). RESULTS: GEE results indicated significant time-group interaction effects on psychological distress (P < 0.001) and sleep quality (P < 0.001). The intervention significantly improved psychological flexibility (β, -2.066; 95% CI, -3.631, -0.500) and reduced perceived stress (β, -2.639; 95% CI, -4.110, -1.169). Psychological flexibility and perceived stress played a mediating role in the observed results. CONCLUSION: GSH-MBIs can improve psychological distress and sleep quality via changing the psychological flexibility and perceived stress in hepatocellular carcinoma patients.