Statins are widely prescribed lipid-lowering agents but are associated with adverse effects such as myopathy and, less commonly, cognitive disturbances. Increasing evidence suggests that plant-derived phytochemicals can interact with statins, producing both beneficial and potentially harmful effects. Preclinical and limited clinical evidence suggests that selected phytochemicals may enhance certain therapeutic effects of statins and may contribute to adverse effect mitigation; however, their potential to support statin dose reduction requires confirmation in well-designed clinical trials. Phytochemicals may reduce inflammation and oxidative stress, potentially enabling lower statin doses. By elucidating these interactions, healthcare providers can develop personalized treatment strategies that enhance therapeutic outcomes of statins while minimizing risks. This review aims to clarify the intricate relationship between specific phytochemicals and statins, emphasizing the need for further investigation into their combined effects on cardiovascular health. The strength of evidence varies considerably across the available literature, ranging from randomized controlled trials to preclinical in vitro and animal studies. Consequently, the translational applicability of many reported phytochemical-statin interactions remains uncertain and warrants further clinical investigation. In addition to potentially beneficial effects, several phytochemicals may pose clinically relevant safety concerns through mechanisms, such as CYP3A4 inhibition, leading to increased statin exposure and toxicity; OATP inhibition, potentially reducing hepatic statin uptake and therapeutic efficacy; and hERG channel blockade, which may increase the risk of QT prolongation. These interactions may contribute to adverse outcomes, including statin-associated myopathy and, in rare cases, rhabdomyolysis.
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