Background: Skin- (SSM) and nipple-sparing (NSM) mastectomies are frequently performed surgeries with a considerable risk for post-operative hematoma or seroma. Tranexamic acid (TXA) is a potent antifibrinolytic drug commonly used in many surgical fields but rather novel in plastic and, specifically, breast surgery. This study investigates the influence of TXA in patients undergoing SSM or NSM with expander-based reconstruction (EbR) on post-operative outcomes. Methodology: A retrospective study was conducted on 132 patients undergoing uni- or bilateral SSM or NSM with EbR between May 2015 and March 2022. Patients receiving systemic TXA treatment for 48 h following a standardized protocol were compared to those who received no treatment. Multivariable linear regression was performed to identify influencing factors and quantify their effect on drainage volume, duration of drain placement, length of hospital stay, post-operative bleeding, and seroma formation. Results: The 132 patients underwent a total of 155 mastectomies (72 in the TXA group, 83 in the control group). TXA significantly reduced drainage volume (-22.3 mL, p = 0.011). Duration of drain placement and length of hospital stay were significantly shorter in the TXA group (p < 0.001 and p = 0.001). No significant side effects were reported. Conclusion: TXA is a safe drug if administered respecting the well-defined contraindications. Systemic TXA administration significantly reduces drainage volume in patients undergoing SSM or NSM and should encourage surgeons to reconsider using drains in post-operative protocols. Duration of drain placement and length of hospital stay were significantly reduced in the TXA group but other factors like resection weight might have a more substantial impact.