Citrus medica L. is rich in numerous vital bioactive constituents, though it is an underutilized among the citrus genus. Therefore, the aim of the present investigation was to evaluate the protective role of the C. medica fruit (CMF) methanol extract against carbofuran (CF)-induced toxicity in experimental rats. In addition, this work aims at detecting and measuring polyphenolic compounds by means of high-performance liquid chromatography (HPLC) and evaluation of the antioxidant activity of this extract. For this, studies dealing with serum hematological and biochemical parameters, liver endogenous antioxidants, as well as hepatic histo-architectural features have been carried out to assess the protective ability of CMF against CF-induced toxicity. Additionally, total phenol, flavonoid, and antioxidant capability were measured and the antioxidant action was investigated using DPPH and nitric oxide radical scavenging assays as well as reducing power assessments. HPLC results revealed the presence of benzoic acid, cinnamic acid, gallic acid, quercetin, and salicylic acid in CMF extract. Furthermore, results showed that CMF has considerable total phenol, flavonoid, and antioxidant capability and exhibits significant free radical scavenging and reducing potentialities. On the other hand, CF intoxication of rats significantly altered the hematological and serum biochemical parameters with hepatocytes disruption. Carbofuran also caused an upsurge in malondialdehyde (MDA) level and a decline in hepatic cellular antioxidant enzymes levels in rats compared to the control group. Co-administration of CMF amended the anomalies and improved the histo-architectural arrangement of hepatocytes in treated groups. CMF also inhibited the alteration of endogenous antioxidant enzymes and MDA levels as compared to the carbofuran treated group and returned them to their normal state. Taken all together, results from this investigation highlight the protective role of CMF against CF-induced toxicity which might be attributed to the polyphenolic constituents of the extract.