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Elevated expression of lysyl oxidase-like 2 (LOXL2) contributes to the malignant tumor progression in multiple cancers. However, the role of LOXL2 in the 5-fluorouracil (5-FU) resistance of colorectal cancer (CRC) remains unclear. This study aimed to explore the effects of LOXL2 on 5-FU sensitivity in CRC. The mRNA and protein levels of LOXL2 were explored in public databases by bioinformatics, validated in clinical tissues using immunohistochemistry, and detected in 5-FU treated cell lines. The 50% inhibitory concentrations (IC50) values were quantified based on the cell viability at different concentrations of 5-FU with CCK-8 assays. Colony formation and flow cytometry assays were performed to measure the proliferation and apoptosis rates. Gene set enrichment and correlation analyses were conducted to identify the probable mechanism of LOXL2 in TCGA samples. Critical molecules of the Hedgehog signaling pathway and anti-apoptotic BCL2 in protein levels were detected with Western blotting. It concluded that LOXL2 was up-regulated and positively linked to the unfavorable prognosis of CRC patients. The LOXL2 expression increased with the rising 5-FU concentrations, especially at 20 and 40 μM. Elevated LOXL2 promoted the resistance to 5-FU, augmented the proliferation, and inhibited 5-FU-induced apoptosis of CRC cells. LOXL2 activated the Hedgehog signaling pathway by promoting the expression of SMO, GLI1, and GLI2, leading to the upregulation of downstream target gene BCL2 in CRC cells. Moreover, the Hedgehog signaling pathway inhibitor cyclopamine blocked the BCL2 upregulation mediated by LOXL2. This study has demonstrated that LOXL2 can reduce 5-FU sensitivity through the Hedgehog/BCL2 signaling pathway in CRC.