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Purpose: To screen the expression of different genes related to oxaliplatin resistance in colorectal cancer (CRC) therapy. Methods: Limma and principal component analysis (PCA) techniques were used to determine genes with significantly different expression levels in the Gene Expression Omnibus (GEO) dataset. A lasso regression model and Venn diagram were used to analyze the intersecting genes. Gene Expression Profiling Interactive Analysis (GEPIA) and the University of Alabama at Birmingham Cancer data analysis Portal (UALCAN) online platform were used to analyze the expression of CYP4F3. The relationship between CYP4F3 expression and survival rate in colorectal cancer was analyzed by Kaplan--Meier curve, while the related pathways involving CYP4F3 were determined by Metascape and gene Ontology-Kyoto Encyclopedia of Genes and Genomes (GO-KEGG) analysis. Furthermore, the correlation between CYP4F3 and TME-related cells was analyzed by Pearson score. In addition, analysis of clinically tested and FDA-approved drugs significantly associated with CYP4F3 was carried out using CellMiner database. Results: PCA and volcano plot analysis indicated there are four upregulated genes and 11 down-regulated genes in oxaliplatin-resistant CRC cells. The intersection gene was CYP4F3 in the lasso regression model and differentially expressed genes (DEG). Moreover, CYP4F3 was upregulated and associated with poor survival in CRC. Gene set enrichment analysis (GSEA), KEGG enrichment, and PPI analysis showed that CYP4F3 and GNG3 are the most significant genes in oxaliplatin-resistant CRC. Furthermore, CYP4F3 expression negatively correlated with the enrichment of T cells, while the expression of CYP4F3 was not associated with drug sensitivity in CRC cells. Conclusion: The findings of this study suggest that CYP4F3 may be a target for the treatment of oxaliplatin-resistant CRC. However, the underlying mechanism of CYP4F3 in the regulation of sensitivity to oxaliplatin needs further investigation. [ABSTRACT FROM AUTHOR]