This study evaluated the effect of thymoquinone (TQ) on the hepatorenal system of rats intoxicated with mercury (HgCl2). Forty male Wistar rats (± 150 g) were randomised into five cohorts (n = 8) and treated for 28 consecutive days as follows: control, HgCl2 (20 µg/L) alone, TQ (5 mg/kg) alone, HgCl2 + TQ1 (20 µg/L + 2.5 mg/kg) and HgCl2 + TQ2 (20 µg/L + 5 mg/kg). Subsequently, HgCl2-induced derangement in the rats’ hepatorenal function was evaluated via biochemical, oxidative, inflammatory, apoptosis biomarkers and histopathological alterations. We observed that co-treatment with TQ preserved organosomatic indices in rats deprecated by HgCl2 treatment alone. TQ reduced hepatorenal biomarkers of toxicity—hepatic transaminases, creatine and urea—in the serum elevated in HgCl2 alone treated rats. TQ averted HgCl2-induced depletion of antioxidant enzymes, glutathione, and total sulfhydryl groups. TQ significantly (p < 0.05) lessened oxidative stress in the examined organs, exemplified by decreased reactive oxygen and nitrogen species, lipid peroxidation, and xanthine oxidase exacerbated by HgCl2 alone treatment. Additionally, TQ enhanced cellular antioxidant response to oxidative stress by increases in thioredoxin, thioredoxin reductase, nuclear factor erythroid 2-related factor-2 and heme oxygenase-1 in HgCl2 co-treated animals. Moreover, TQ alleviated HgCl2-induced inflammation by significantly downregulating myeloperoxidase, nitric oxide, and interleukin-10 and assuaged apoptosis by decreasing caspase-3 and caspase-9 activities in the experimental rat hepatorenal system. Additionally, TQ interacted with the binding packets of Keap1 and TBK with low Kd values of 4.63 × 10⁻5 M and 1.54 × 10⁻4 M, respectively. Taken together, the findings of this study demonstrate the likely protective benefit incumbent on TQ as an antioxidant, anti-inflammatory and anti-apoptotic compound conferring protection against chemical-induced hepatorenal toxicity, including HgCl2 in this instance.