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Background: Chronic sinusitis, nasal polyps, and other sinus-related illnesses are common conditions that can be treated with endoscopic sinus surgery (ESS). However, some patients may experience pain or discomfort after the procedure. Pre-emptive analgesia is a method used to reduce post-operative discomfort and the need for painkillers. Recently, there has been growing interest in studying the potential use of nalbuphine and dexmedetomidine as preventative analgesics in ESS. Aims and Objectives: This study aimed to determine the effectiveness of nalbuphine and dexmedetomidine in reducing post-operative pain and opiate use in ESS patients, a randomized controlled trial. Materials and Methods: Ninety patients were randomly selected and given nalbuphine, dexmedetomidine, or a placebo before anesthesia induction. Pain ratings, opioid use, and adverse effects were monitored during the post-operative period. Results: The results showed that both nalbuphine and dexmedetomidine significantly reduced post-operative pain ratings and opioid usage compared to the placebo. Dexmedetomidine was found more effective than nalbuphine in reducing pain, and patients who received it experienced less nausea and vomiting in the first few days after surgery. However, the occurrence of sedation or respiratory depression was not significantly different among the groups. Conclusion: The study concludes that nalbuphine and dexmedetomidine can effectively reduce post-operative pain and opiate use in ESS patients as preventative analgesia. Dexmedetomidine may be a better option due to its superior analgesic effect and lower incidence of nausea and vomiting. These findings may lead to improved pain management and patient satisfaction following ESS procedures.