Objective To investigate the effect of S-adenosylmethionine (SAMe) on Janus kinase 2/ signal transducer and activator of transcription 3 (JAK2/STAT3) pathway and liver fibrosis in patients with alcoholic liver disease (ALD). Methods A total of 96 ALD patients admitted to Nanyang First People's Hospital from September 2023 to September 2024 were prospectively selected as the research objects, and a randomized controlled trial was designed. They were divided into the routine group and the experimental group by the simple random number table method, with 48 cases in each group. The conventional group was treated with conventional drug therapy, and the experimental group was treated with SAMe combined with conventional drug therapy. The expression levels of JAK2/STAT3 protein, inflammatory indicators, oxidative stress indicators, and liver fibrosis indicators of the two groups were compared 1 day before and 1 day after treatment. The patients were followed up for one year after treatment, and the recovery of liver function was compared between the two groups. The correlation between JAK2/STAT3 pathway proteins and clinical indicators was analyzed. Results After treatment, the expression levels of JAK2 and STAT3 in the experimental group were lower than those in the conventional group (P<0.05). The expression levels of interleukin-6 (IL-6), interleukin-1β (IL-1β) and reactive oxygen species (ROS) in the experimental group were lower than those in the conventional group, and the expression level of glutathione (GSH) was higher than that in the conventional group (P<0.05). The experimental group had significantly lower expression levels of procollagen type Ⅲ amino terminal peptide (PⅢNP), collagen type Ⅳ (C-Ⅳ), hyaluronic acid (HA), and laminin (LN) than the conventional group (P<0.05). At the end of follow-up, the expression levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil) in the experimental group were lower than those in the conventional group (P<0.05). JAK2 and STAT3 were positively correlated with IL-6, IL-1β, ROS, PⅢNP, C-Ⅳ, HA, LN, respectively, and negatively correlated with GSH (P<0.05). Conclusion SAMe can reduce inflammatory response and oxidative stress injury in patients with ALD, and has a positive effect on delaying the process of liver fibrosis and promoting the recovery of liver function. Its mechanism may be closely related to the inhibition of JAK2/STAT3 pathway.