Abstract Background Opioids have historically been a first-line therapy for surgical pain control. They were considered optimum and the mainstay for balanced anesthesia but recently the concerns about their side effects were raised. The concept of opioid free anesthesia (OFA) was introduced to provide a safer alternative that would provide benefits to selective group of patients as well as enhance recovery after surgery. Methods The current study compares the use of a mixture of dexmedetomidine and ketamine infusion with traditional fentanyl infusion intra-operative on many variables both intra-operative and post- operative in laparoscopic surgeries. Number of patients who will need rescue narcotics after extubation and total nalbuphine consumption, hemodynamic events (bradycardia, hypotension and hypertension), time to extubation, time to reach Alderete score of 9, post-operative hypoxemia, vomiting, pain scores were recorded and compared with the traditional balanced anesthesia (TBA). Results Forty patients were enrolled in the study, 20 patients in each group. The 2 groups, TBA and OFA, were comparable in demographic data (age, sex, body mass index (BMI), lean body weight (LBW)) and duration of surgery. There was significant decrease in pain scores, number of patients who will need rescue narcotics after extubation and nalbuphine consumption in the OFA group that extended to 24 h post-operative. TBA group showed statistically significant less time needed for extubation (P-value 0.018) and reaching Aldrete score of 9 (P-value 0.02). Conclusions OFA has a better profile than TBA as regard to post-operative pain score and opioid consumption post-operative but they have relative increase in time to extubation and time to reach Aldrete score of 9, and they were equally safe regarding post operative hypoxia and hemodynamics.