Background/Objectives: Tissue expander (TE)-based breast reconstruction is a common procedure, but postoperative infection rates can reach up to 30%. The optimal skin antiseptic solution for minimizing these infections remains uncertain. This retrospective cohort study aimed to compare the impact of chlorhexidine and povidone-iodine for skin antisepsis in preventing surgical site infections in patients who underwent TE-based breast reconstruction. Methods: The TriNetX database was queried to identify patients who underwent TE-based breast reconstruction. Patients were classified into two cohorts: the chlorhexidine group and the povidone-iodine group. A propensity score matching analysis was performed to control infection risk factors. The primary outcome was the occurrence of surgical site infections, while secondary outcomes included wound dehiscence, emergency department visits, debridement, and TE removal. All outcomes were assessed at 30, 60, and 90 days following surgery. Results: After matching of both the chlorhexidine cohort and povidone-iodine cohort, each consisted of 1446 patients. Within 30 days post-surgery, no significant differences were observed between the chlorhexidine and povidone-iodine groups in terms of the risk of surgical site infections (RR 0.62, p = 0.168), wound dehiscence (RR 1.00, p = 1.000), emergency department visits (RR 0.95, p = 0.700), debridement (RR 0.71, p = 0.271), or TE removal (RR 0.84, p = 0.335). Similar results were seen at 60 and 90 days post-surgery. Conclusions: This study suggests that chlorhexidine and povidone-iodine may be equally effective for skin antisepsis in preventing surgical site infections and associated complications in patients undergoing TE-based breast reconstruction.