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ABSTRACT Background Chemotherapy drugs may lead to hepatic injury, which is considered one of the limitations of these drugs. Objectives The aim of this study was to evaluate the effect of quercetin (QUE) on M1/M2 macrophage polarization and hepatoprotective effect in cyclophosphamide (CTX)‐induced liver toxicity. Methods Twenty‐four mice were divided into four groups (Control, QUE, CTX, CTX + QUE). The CTX and CTX + QUE groups received 200 mg/kg CTX. The animals in the QUE and CTX + QUE groups received 50 mg/kg QUE. All animals were sacrificed, and serum and liver samples were used for laboratory analyses. Results Examinations indicated that CTX exposure led to disruption of liver functions and morphological degenerations. Tissue pro‐apoptotic Bax and caspase 3, pro‐inflammatory TNF‐α and IL‐1β, transcription factor NF‐κB, and M1 macrophage polarization marker CD86 were upregulated significant (p 0.05) to the control and QUE groups. The M1 cell surface marker expression of CD86 is significantly (p