We previously characterized the volatile compounds of black pepper (Piper nigrum) essential oil (BPEO) and demonstrated its mitigating effect against dexamethasone-induced pancreatic damage. Herein, we investigated the protective effect of the oil against dexamethasone-induced hepatotoxicity in rats and pinned the possible underlying mechanisms. In the in vivo experiment, male Wistar rats were divided into five groups. The first group served as the normal control receiving a saline solution (Control). The second group was subjected to hepatic damage through dexamethasone exposure (Dexa) at 10 mg/kg. The third group received both dexamethasone and metformin (Met) at a dose of 50 mg/kg. The remaining two groups were exposed to dexamethasone along with black pepper oil administration at low and high doses (BPEO, 0.5 mL/kg and 1 mL/kg). We showed that BPEO offset toxicity manifestations, as indicated by reducing monocyte infiltration, hepatocyte degeneration and vacuolation, and reduction of ALT and AST levels. Moreover, relative to the dexamethasone-treated rats, BPEO declined the number of PGC-1α positive hepatocytes and activated the expression of PPAR-α in the liver. BPEO showed comparable hepatoprotective potency to the standard drug, metformin, especially at the higher dose tested (1 mL/kg). This study showcases the promising potential of BPEO in thwarting dexamethasone-induced adverse effects on the liver by alleviating hepatic biomarkers hikes and preventing histopathological changes and fibrosis. Finally, it opens a new avenue on the potential role of BPEO in modulating steroid-induced hepatic injury through the PGC-1α/ PPAR-α pathway.