Aim: This prospective, randomized, double-blind study compared the efficacy and safety of dexketoprofen trometamol (DT) and paracetamol in managing post-operative pain for patients undergoing intravenous regional anesthesia (IVRA) during hand surgery. Methods: Sixty-six ASA I-II patients aged 18-70 were enrolled after exclusion criteria, including drug allergies, psychiatric disorders, Raynaud’s disease, and anticoagulant therapy. Patients were randomized into two groups: Group 1 received 25 mg DT, and Group 2 received 500 mg paracetamol for post-operative pain relief. At home post-operatively, pain intensity was assessed using the visual analog scale (VAS), and rescue analgesia was provided if needed. Patients recorded pain relief efficacy, satisfaction levels, side effects, and tablet consumption over 30 hours. Results: Although both drugs provided adequate post-operative pain control, significant differences were found. Analgesic efficacy was significantly higher in Group 1 (p = 0.001), and patient satisfaction was significantly higher than in Group 2 (p = 0.003). While 75.8% of patients in Group 1 reported complete pain relief, this rate was recorded as 42.4% in Group 2. Additionally, the post-operative morphine requirement was significantly lower in Group 1 (p = 0.04), highlighting the potential of DT to reduce opioid use. The frequency of adverse events such as nausea, vomiting, headache, and insomnia was similar between the groups. It did not show statistically significant differences (p > 0.05), supporting the safety of both drugs. Conclusions: DT offers superior post-operative pain control, reduced opioid reliance, and higher patient satisfaction compared to paracetamol following IVRA in ambulatory hand surgery. These findings support DT as a promising alternative to paracetamol in multimodal analgesic strategies. Additional studies are needed to confirm these findings and examine the mechanisms behind the differences in observed outcomes. The choice of analgesic should remain patient-specific, considering individual clinical conditions, contraindications, and preferences.