OBJECTIVE: Despite its evident renal toxicity, vancomycin is considered an effective glycopeptide antibiotic against life-threatening positive bacterial contagions. The current study aimed to investigate the potential protective effects of carvacrol as well as its underlying mechanism against vancomycin-induced nephrotoxicity. MATERIALS AND METHODS: The animals were randomly classified into four groups (8 rats per group). Group I, which served as a control group, received only vehicles. Group II received a single i.p. injection of 50 mg/kg of carvacrol for seven days. Group III received vancomycin (200 mg/kg, i.p.) as a singular daily dose for seven days. Carvacrol was administered to Group IV seven days prior to the daily vancomycin dose. RESULTS: The results revealed that carvacrol minimized vancomycin-induced renal injury as evidenced by lower serum cystatin C levels and kidney injury molecule-1 (KIM-1), in addition to a decline in renal damage caused by vancomycin as indicated in histopathological assessment. Furthermore, carvacrol significantly attenuated oxidative stress parameters and inflammatory mediators. Moreover, it downregulated Keap1, mitogen-activated protein kinase (p38MAPK), and nuclear factor kappa B (NF-κB) genes and proteins, along with controlling the NF-κB inhibitory protein (IkBα) and nuclear factor erythroid 2-related factor 2 (Nrf2) genes and proteins observed through streaming its genes. A molecular docking technique was also used to investigate the potential interactivity between carvacrol and proteins involved in regulating oxidative injury and inflammatory responses. CONCLUSIONS: The current study findings revealed that carvacrol administration before vancomycin could be a promising therapeutic approach for maceration of renal damage stimulated by vancomycin via controlling IkBα/MAPK and Keap1/Nrf2 signaling molecules.