Introduction: Post-operative pain management following total knee replacement (TKA) is crucial. The introduction of some available, inexpensive, and effective methods for post-operative pain management is necessary. Therefore, this randomized clinical trial was done comparing the analgesic effect of an oral low-cost drug (oxycodone) and ultrasound-guided nerve block (saphenous nerve block) to assess the best method for post-operative pain management after TKA surgery. Methods: This single-blind, randomized, controlled, single-center clinical trial was performed from June 2017 to June 2018. There were 80 patients undergoing TKA randomly divided into two groups,group A received a single shot ultrasound-guided saphenous nerve block and, group B took oxycodone which started before and continued every 6 hours after surgery to control post-operative pain. The pain score by visual analog scale (VAS), nausea-vomiting, and diclofenac use were assessed postoperatively at 2, 6, 12, and 24 hours’,post-spinal anesthesia administration. Data were analyzed by SPSS-21, Chi2, Fishers' exact test, and Mann-Whitney test were used for comparing data between the two groups. Result: The pain intensity according to the visual analog scale at 2, 6, 12, and 24 h post-operative was 1. 25±, 1. 37, 4. 12±, 1. 11, 5. 25±, 0. 89, and 4. 57±, 095 in group A, and 1. 10±, 0. 953. 77±, 0. 99, 4. 05±, 0. 78, and 2. 95±, 0. 78 in the group B, respectively,this was significantly lower in group B at 12 and 24 hours (P<0. 05). The mean diclofenac use was 87. 01±, 68. 02 mg in group B and 262. 04±, 92. 05 mg in the group A (P<0. 001). Also, the incidence of nausea and vomiting was significantly higher in group B compared to group B (P<0. 001). Conclusion: Oral oxycodone can control post-operative pain better than saphenous nerve block in the management of post-operative pain and reducing total additional analgesic drug consumption. Although, adverse effects such as nausea and vomiting were lower in saphenous nerve block.