Aim: The aim of this study was to compare the effects of dexmedetomidine, midazolam, propofol, and intralipid on lidocaine-induced cardiotoxicity and neurotoxicity. Methods: Forty-eight male Sprague-Dawley rats were randomly divided into six groups (n = 8 per group): control (C), lidocaine (L), lidocaine + dexmedetomidine (LD), lidocaine + midazolam (LM), lidocaine + propofol (LP), and lidocaine + intralipid (LI). Dexmedetomidine (100 μg/kg), midazolam (4 mg/kg), propofol (40 mg/kg), and intralipid (10 mg/kg) were administered intraperitoneally as pretreatment. Lidocaine (90 mg/kg) was administered intraperitoneally to induce oxidative stress in all groups except the control. After 60 minutes of electrocardiography (ECG) recording, the rats were sacrificed, and heart and brain tissue samples were collected. Comparative measurements of total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), and inflammatory parameters were conducted. Results: In heart tissue samples, TAS was significantly higher in LI and LD groups (p < 0.05). Additionally, oxidative stress was significantly higher in the LM group (p < 0.05). Despite an increase in oxidative stress in brain tissue samples across all groups, it was found that all groups exhibited antioxidant protective effects (p < 0.05). Inflammatory parameters in heart and brain tissues significantly decreased in all groups, especially in the LI group (p < 0.05). Conclusion: It was observed that pretreatment with midazolam increased oxidative stress induced by lidocaine, while dexmedetomidine and intralipid exhibited greater antioxidant effects. Dexmedetomidine and intralipid used as pretreatment were shown to be more effective in protecting against oxidative stress and inflammation.