The present study aimed to evaluate the antioxidant protective effects of the herbal extract of Crepis rueppellii (CR) against paracetamol (PCM)– induced nephrotoxicity in guinea pigs using hematological, biochemical, histological, and immunohistochemical methods. Thirty guinea pigs were divided into six groups: control, PCM (2 g/kg), CR1 group (100 mg/kg), CR2 group (200 mg/kg), CR1 (100 mg/kg) + PCM, and CR2 (200 mg/kg) + PCM. The hematological results showed that the PCM-treated groups experienced significant reductions in Hb, red blood corpuscles, packed cell volume, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, white blood cell, platelets, neutrophils, lymphocyte, and monocyte, in addition to albumin and total protein levels compared with the control group. In contrast, the groups treated with CR showed increases in all the abovementioned parameters. Morphologically, kidney tissues of PCM and CR-treated groups showed focal leukocytic infiltrations and extensive necrosis, while CR1 + PCM- and CR2 + PCM-treated groups revealed more pathological changes than PCM alone. The Bax immunohistochemical reaction showed strong positive reactions in both the PCM and CRtreated groups, while the CR + PCM-treated groups displayed very strong positive compared with the PCM-only group. In conclusion, the results from the hematological and biochemical parameters indicated that CR extract had an ameliorative effect against PCM toxicity.