OBJECTIVE: To assess the independent and combined associations of tumor-related psychiatric symptoms (TRPS) with dynamic health-related quality of life (HRQL) in patients with hepatocellular carcinoma (HCC) after hepatectomy and to identify related patterns of health behaviors. METHODS: This prospective study included patients with HCC who underwent hepatectomy between September 2021 and May 2022. Independent and combined associations between TRPS and HRQL were identified by generalized linear model and weighted quantile sum model, respectively. Trajectories of HRQL were identified by latent class mixed model. RESULTS: Among the 205 patients, 174 (84.9%) were male. For the outcome of HRQL at 6 months: Anxiety, depression, fatigue, and sleep disorder were independently associated with a decrease of HRQL (all P < 0.05). A negative combined effect of TRPS was also found (β =  - 5.07, 95% CI, - 10.01 to - 0.13), with depression emerged as the predominant contributor (49%). The health behaviors of body mass index, smoking, drinking, or physical exercise were not significantly modified the associations between combined TRPS and HRQL (all P > 0.05 for interaction). Similar results were also found for the HRQL at baseline and at 1 and 3 months. Three HRQL trajectory groups were identified: recover (44.9%), poor (44.4%), and deteriorating (10.7%). Deteriorating group was associated with higher incidence of TRPS (all P < 0.05). CONCLUSIONS: TRPS were associated with a decrease of HRQL regardless of healthy behaviors in HCC patients. Therefore, healthy behaviors promotion alone might not substantially increase HRQL associated with TRPS, and other measures tackling TRPS are warranted.