Diverse clinical observations and basic studies have been conducted to explore the implications of analgesic medications in liver diseases. However, the direct causal relationship between prescription analgesic use (PAU) and the risk of liver cancer and precancerosis remains unclear. Thus, we aimed to reveal the conceivable causal effect of PAU on liver cancer and precancerosis, with immune cells as mediating factors. Two-sample Mendelian randomization (MR) analyses were performed to ascertain the causality of PAU on liver cancer and precancerosis. Sensitivity analysis approaches were employed to assess the heterogeneity and pleiotropy of results. Our findings revealed a causal correlation between different PAUs and the risk of liver cancer and alcoholic liver disease (ALD). Specifically, salicylic acid derivatives (SADs) and anilide medications were found to have a protective effect on liver cancer. And non-steroidal anti-inflammatory drugs (NSAIDs) and anilide medications showed a causal impact on ALD. Finally, mediation analyses found that anilide medications influence liver cancer through different immune cell phenotypes. Our research provides new genetic evidence for the causal impact of PAU on liver cancer and precancerosis, with the mediating role of immune cells demonstrated, offering a valuable foundation for researching analgesic medications in liver cancer and precancerosis treatment.