Study objective Moderate to severe postoperative pain occurs in up to 60% of women following breast operations. Our aim was to perform a network meta-analysis and systematic review to compare the efficacy and side effects of different analgesic strategies in breast surgery. Design Systematic review and network meta-analysis. Setting Operating room, postoperative recovery room and ward. Patients Patients scheduled for breast surgery under general anesthesia. Interventions Following an extensive search of electronic databases, those who received any of the following interventions, control, local anesthetic (LA) infiltration, erector spinae plane (ESP) block, pectoralis nerve (PECS) block, paravertebral block (PVB) or serratus plane block (SPB), were included. Exclusion criteria were met if the regional anesthesia modality was not ultrasound-guided. Network plots were constructed and network league tables were produced. Measurements Co-primary outcomes were the pain at rest at 0–2 h and 8–12 h. Secondary outcomes were those related to analgesia, side effects and functional status. Main results In all, 66 trials met our inclusion criteria. No differences were demonstrated between control and LA infiltration in regard to the co-primary outcomes, pain at rest at 0–2 and 8–12 h. The quality of evidence was moderate in view of the serious imprecision. With respect to pain at rest at 8–12 h, ESP block, PECS block and PVB were found to be superior to control or LA infiltration. No differences were revealed between control and LA infiltration for outcomes related to analgesia and side effects, and few differences were shown between the various regional anesthesia techniques. Conclusions In breast surgery, regional anesthesia modalities were preferable from an analgesic perspective to control or LA infiltration, with a clinically significant decrease in pain score and cumulative opioid consumption, and limited differences were present between regional anesthetic techniques themselves.