BACKGROUND: Colorectal liver metastasis (CRLM) is the most frequent form of metastasis and the main reason for deaths associated with colorectal cancer. However, prognostic biomarkers originating from CRLM tissue remain limited. Additionally, the impact of the metabolism-associated gene SLC38A4 on patients with CRLM remains elusive. METHODS: Metabolism-related differentially expressed genes (MRDEGs) were identified between CRLM and adjacent normal liver (NL) tissues using GEO datasets (GSE38174, GSE41258). The prognostic significance of these MRDEGs in CRLM (GSE159216) was evaluated using Cox regression and Kaplan-Meier survival analyses. The differential expression of SLC38A4 was validated through multiple experiments, including qRT-PCR, Western blotting, and immunohistochemistry. Genes co-expressed with SLC38A4 were identified through a weighted gene co-expression network analysis, and enrichment analyses were conducted by clusterProfiler. The link between SLC38A4 and immune infiltration was assessed with the CIBERSORT algorithm, while drug sensitivity was analyzed using oncoPredict. RESULTS: SLC38A4 was identified as an independent favorable-prognosis biomarker for CRLM, with significantly lower expression in CRLM compared to NL tissues. Enrichment analyses indicated that SLC38A4-associated genes participate in diverse metabolic processes. Immune infiltration analysis indicated that SLC38A4 expression is linked to the infiltration of immune cells and three immune checkpoint genes: ARG1, EDNRB, and TNFSF4. Additionally, multiple anti-tumor drugs were positively associated with SLC38A4 expression. CONCLUSION: Elevated SLC38A4 expression is correlated with a favorable prognosis in CRLM, likely through mechanisms involving metabolic reprogramming and immune infiltration. Thus, SLC38A4 may serve as both a prognostic biomarker and a potential biomarker for future therapeutic investigation, offering new precision medicine options for CRLM patients.