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This review examined the association between calcineurin inhibitor (CNI) exposure and de novo malignancy risk in liver transplant recipients. A comprehensive electronic search was conducted in PubMed, Medline and Cochrane Library until April 2025. All the articles obtained were then included in the review if they met the inclusion criteria. A total of nine studies with a population of 6829 recipients investigating the association between CNI exposure and increased malignancy risk were included in the review. Some studies revealed divergent risks between CNI types, for instance the association of cyclosporine with higher solid tumour risk compared with tacrolimus. A single study reported a potential dose-dependent relationship, suggesting high tacrolimus exposure was associated with a 1.71-fold to 2.3-fold increase in de novo malignancy risk. The narrative synthesis of the nine included studies revealed a predominant association between CNI and non-melanoma skin cancer and upper aerodigestive cancers. Among the key risk factors associated with increased de novo malignancies in patients treated with CNIs are age (>60 years), male gender, smoking history and time since transplantation correlating with malignancy incidence. Two individual studies reported that CNI minimisation strategies, including early withdrawal protocols, were associated with reductions in malignancy incidence ranging from 35% to 42% for combination therapy with malian target of rapamycin (mTOR) inhibitors. In one study, conversion to mycophenolate mofetil monotherapy was associated with an 84% reduction in malignancy risk. These findings support personalised immunosuppression approaches tailored to individual risk profiles. Nonetheless, further prospective studies are needed to optimise CNI regimens that balance rejection prevention and long-term oncological safety. PROSPERO registration number : CRD420251082749.