Pentachloronitrobenzene (PCNB) is an organochlorine-fungicide that is mostly applied on soil and seeds. Many reports have proven that it is still found in soil and food product samples. This study aimed to evaluate the phytochemical profile of the Rheum rhabarbarum L. (RRL) and its protective effect against PCNB in experimental rats. The LC/MS2 results indicated that the RRL extract contained 18 active components identified by the LC/MS2 data as polyphenolic, hydroxyl stilbenes, anthraquinones, and naphthalenes compounds. The exposure to PCNB induced oxidative stress by decreasing antioxidant markers and surged MDA and NO. PCNB markedly raised the NF-κB, and caspase 3 while significantly reducing the BcL2. Moreover, liver tissues exposed to PCNB showed downregulated antioxidants-related genes (sod1, cat, and gst), increased pro-inflammation genes (tnf-α, il-6, and il-1β), and apoptosis genes. Additionally, the PCNB treatment resulted in detrimental pathological effects on the liver and kidney tissues. The simultaneous treatment of RRL and PCNB exerted hepatorenal protective effects by improving clinical symptoms in liver and renal tissues, via restoring all tested parameters, and pathological issues. Altogether, the obtained findings show that RRL extract may offer an effective strategy for ameliorating PCNB-induced hepatorenal toxicity via alleviating oxidative stress, inflammation, and apoptosis at treatment doses of 100 and 200 mg/kg b.w. orally.