Synthetic insecticide fipronil (FPN) is widely spread worldwide for controlling insects in agriculture and public health sectors. Thus, this work aimed to study the molecular mechanisms of FPN induced hepatotoxicity and the protective role of fish oil in female rats. Female rats were allocated in four groups of rats exposed to FPN and/or fish oil and control. Oxidative stress markers i.e., lipid peroxidation (LPO), antioxidant enzymes, and liver function enzymes, butyryl cholinesterase (BuChE), histopathological lesions, DNA damage, expression alteration of apoptosis and inflammatory related genes in liver tissues were assessed. FPN treatment induced significant changes in the levels of LPO, liver function, BuChE, histopathological lesions, over-expression of tested genes and elevation in DNA damage. In contrary, treatment of FPN-exposed rats with fish oil improved significantly the negative effects of FPN on liver tissues. The molecular mechanisms of FPN might be due to the formation of reactive oxygen species (ROS) and change the oxidant/antioxidant statues. The hepatoprotective effect of fish oil might be attributed to increase the antioxidant capacity prevented the ROS generation induced by FPN in female rats.