Drug-induced liver damage is a frequent adverse effect and a putative contributor to the acute liver damage associated with methotrexate (MTX) use. Both sodium/glucose cotransporter (SGLT2) inhibitor, empagliflozin (EMPA) and dihydrochalcone flavonoid, neohesperidin (NHD) have promising standards for abrogating oxidative stress, apoptosis, and inflammation. In the current study, we suggested that NHD and EMPA could show protecting properties against MTX-prompted liver harm while considering N-acetylcysteine (NAC) as a reference agent. To investigate our hypothesis, an experimental adult male rat model comprising of 70 rats divided randomly into 7 groups, was implemented. The impacts of MTX (20 mg/kg, once, i.p.), alone or with orally administered NHD (40 and 80 mg/kg), EMPA (10 and 30 mg/kg), and NAC (150 mg/kg) were assessed and paralleled to control group that received vehicle. Pretreatment with NHD and EMPA demonstrated marked enhancement in liver function aberrations, histopathological deterioration, and hepatic oxidative stress injuries, along with considerable downregulation of inflammatory cytokines TNF-α and IL-6. NHD and EMPA also showed notable decreases in NF-ĸB, Keap-1, caspase-3, and HSP70 expression levels, and an increase of Nrf2, PPARγ, and O-1 expressions. This investigation shows that both NHD and EMPA can mitigate oxidative injuries, apoptosis, and inflammation in hepatic tissues of MTX-remedied animals, primarily by the beginning of Nrf2/PPARγ/HO-1 signaling and suppression of NF-ĸB/IL-6/HSP70/TNF-α pathways. Both drugs represent a unique class that alleviates or at minimum impedes the starting of toxicity elicited by MTX; and may act as a promising therapeutic target for clinical use in the future.