Polystyrene microplastics (PS-MPs) are environmental toxicants that impose adverse effects on organisms. Rhamnetin (RHM) is a natural flavone that shows multiple therapeutic potentials. Therefore, the present study was planned to determine the mitigative effect of RHM against PS-MPs induced liver damage. 48 rats were divided into 4 groups. Control group, PS-MPs (0.01 mg/kg) administered group, PS-MPs (0.01 mg/kg)+ RHM (50 mg/kg) co-administered group and RHM alone (50 mg/kg) administered group. PS-MPs reduced the expressions of Nrf-2 and anti-oxidant gene expressions, whereas increasing the Keap-1 expression. PS-MPs also lowered the activities of catalase (CAT), glutathione reductase (GSR), heme oxygenase-1 (HO-1), glutathione-S-transferase (GST), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione (GSH), besides elevated the MDA and ROS levels. Additionally, PS-MPs augmented alanine transaminase (ALT), alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels. Furthermore, there was an upsurge in the levels of inflammatory indices in PS-MPs treated group. PS-MPs intoxication also increased Bax and Caspase-3 expression, whereas lowering the Bcl-2 level. Nevertheless, RHM mitigated all the anomalies due to its hepatoprotective, anti-inflammatory, anti-oxidant and anti-apoptotic potentials. The supplementation of RHM regulates the apoptotic as well as inflammatory pathways and protects the liver from damage.