Background: Regional nerve blocks are an integral part of multimodal analgesia and should be chosen based on their efficacy, convenience, and minimal side effects. Here, we compare the use of pectoral (PEC II) and serratus-intercostal fascial plane (SIFP) blocks in breast carcinoma cases undergoing modified radical mastectomy (MRM) in terms of the postoperative analgesic efficacy and shoulder mobility. Methods: The primary outcome of this prospective controlled study was to compare the postoperative static and dynamic pain scores, and the secondary outcome was to assess the shoulder pain, range of shoulder joint motion, and hemodynamic parameters. Sixty patients were randomly allocated to three groups and given general anesthesia. All patients received paracetamol, diclofenac, and rescue doses of tramadol based on the Institute's Acute Pain Service (APS) policy. No block was performed in group C (control), whereas groups P and S received PEC II and SIFP blocks, respectively, before surgical incision. Results: The groups were comparable in terms of age, weight, height, and body mass index distribution (P > 0.05). Dynamic pain relief was significantly better 12 and 24 h postoperatively in groups P (P = 0.034 and P = 0.04, respectively) and S (P = 0.01 and P = 0.02, respectively) compared to group C. Shoulder pain relief and shoulder mobility were better in group S, while the hemodynamic parameters were more stable in group P. Conclusions Both SIFP and PEC blocks have comparable dynamic and static pain relief with better shoulder pain scores in patients receiving SIFP.