Abstract Background Breast cancer surgery is associated with considerable acute post-surgical pain and restricted mobility. Various regional and neuraxial anesthesia techniques have been used to alleviate post-mastectomy pain. Ultrasound-guided serratus anterior plane block (SAPB) has been considered a simple and safe technique. This randomized control study was performed to compare the efficacy of SAPB with the thoracic paravertebral block (TPVB) for postoperative analgesia after breast cancer surgery. Methods A total of 40 adult ASA physical status I - II female patients undergoing radical mastectomy were randomly allocated into two groups to receive either ultrasound-guided TPVB or SAPB with 0.4 mL.kg-1 0.5% ropivacaine, 30 min before surgery. All patients received standardized general anesthesia for surgery. Injection diclofenac and tramadol were used for postoperative rescue analgesia. The time to first rescue analgesia, total analgesic consumption in the first 24 hours, postoperative pain scores, and any adverse effects were recorded. Results The time to first rescue analgesia was significantly longer in the SAPB group (255.3 ± 47.8 min) as compared with the TPVB group (146.8 ± 30.4 min) (p< 0.001). Total diclofenac consumption in 24 hours was also less in the SAPB group (138.8 ± 44.0 mg vs 210.0 ± 39.2 mg in SAPB and TPVB group respectively, p< 0.001). Postoperative pain scores were significantly lower in the SAPB group as compared with TPVB group (p< 0.05). The incidence of PONV was also less in the SAPB group (p= 0.028). No block-related adverse effects were reported. Conclusion We found that the serratus anterior plane block was more effective than the thoracic paravertebral block for postoperative analgesia after breast cancer surgery.