Background Hepatocellular carcinoma (HCC) is the second leading cancer‐related cause of mortality worldwide. Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), are commonly used worldwide. Available evidence investigating the association between SSRIs use and HCC risk is limited. Objective The present study aimed to investigate if the effect of all kinds of SSRIs on HCC was the same or not using population‐based study. Methods The nationwide population‐based study herein using Taiwan's National Health Insurance Research Database included a total of 59 859 cases with HCC and 285 124 matched controls. Conditional logistic regression analyses were adjusted for confounding variables. Results All common kinds of SSRIs including fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine were associated with lower HCC risk, and the findings were dose‐dependent (eg, fluoxetine: 1‐28 DDD [defined daily dose]: adjusted odds ratio [aOR]: 0.81, 95% confidence interval [CI], 0.73‐0.89; 29‐365 DDD: aOR: 0.71, 95% CI, 0.64‐0.79; and ≥366 DDD: aOR: 0.55, 95% CI, 0.45‐0.67) (P for trend < .001). Conclusions All kinds of SSRIs were associated with decreased risk of HCC.