Background and Objective Globally, postpartum hemorrhage (PPH) remains the most common direct cause of maternal mortality. This study evaluated the feasibility and acceptability of introducing heat-stable carbetocin (HSC) for PPH prevention and tranexamic acid (TXA) for PPH treatment in five Sub-Saharan African countries following recent World Health Organization (WHO) recommendations. This study also assessed healthcare providers’ (HCPs’) favorability toward using these medicines. Methods We conducted a mixed methods pilot implementation study in selected facilities across Burkina Faso, Ethiopia, Ghana, Sierra Leone, and Uganda between May and December 2022. We compared baseline data obtained from patient registers with data collected during implementation on the safe and appropriate use of HSC and TXA using descriptive statistics. HCP responses were analyzed qualitatively using a thematic analysis. Results Following training, HSC was administered prophylactically in 11,329 (92.4%) of 12,262 deliveries in all study facilities which received a uteorotonic for PPH prevention during implementation and was used safely and appropriately. TXA administration for PPH treatment was done safely, appropriately, and within the WHO-recommended time. No adverse events were reported throughout the study. HCPs overall showed high confidence in, and favorability toward, using both medicines. Conclusion and Global Health Implications Our study demonstrated that HSC and TXA can be safely and appropriately implemented in primary and tertiary facilities, and their introduction is feasible and acceptable from the perspective of HCPs. A holistic approach to training and regular supportive supervision is needed to ensure the continued safe use of these new and lesser-utilized PPH medicines. Dedicated training is required to improve the documentation of patient charts on PPH care. Introducing these medicines holds promise for improving PPH care in low- and middle-income countries, including by addressing suboptimal efficacy due to cold chain system challenges.