This study examined the effect of supply chain optimization on the operational efficiency of manufacturing firms in South-East Nigeria, with specific focus on inventory management, logistics and distribution, and supplier relationship management. The study adopted a survey research design, and data were collected through structured questionnaires administered to 109 employees of selected firms, out of which 102 responses were valid for analysis. Data were analyzed using descriptive statistics and regression analysis. The results revealed that inventory management optimization had a significant positive effect on operational efficiency (β = 0.322, p = 0.001), logistics and distribution optimization also showed a significant effect (β = 0.287, p = 0.001), while supplier relationship management had the strongest influence (β = 0.341, p = 0.000). The study concluded that effective supply chain optimization significantly improves operational efficiency by reducing delays, minimizing costs, and enhancing productivity. It was therefore recommended that manufacturing firms strengthen supplier relationships, improve inventory systems, and adopt efficient logistics strategies to achieve better operational performance.