Cassava is a crucial food and economic crop in tropical regions globally. In response to challenges in fertilizer use efficiency for cassava cultivation, which is traditionally compromised by extensive leaching and broad root zone distribution, a novel large-particle slow-release fertilizer (LPF) was developed in this study. This fertilizer was synthesized through solution polymerization using non-metallic minerals and seaweed extract. Compared to conventional SFs that release 99% of nutrients within 1 min, the LPF prolonged the release duration to 51 min under optimal synthesis conditions: drying temperature of 80 °C, total extrusion force of 40 t, drying air pressure of −0.40 bar, auxiliary mineral proportion of 50%, and water content of 15%. Microbeam characterization (e.g., FTIR) and kinetic modeling revealed that the superior performance of LPF resulted from mineral crystal enrichment in the outer layer of fertilizer granules, facilitating intra-particle diffusion processes and imposing boundary layer limitations on nutrient release (e.g., N, P, and K). Field experiments validated the slow-release performance of the fertilizer. Notably, soil treated with LPF exhibited superior nutrient retention in the topsoil layer (0–20 cm) both horizontally and vertically. Even with two-thirds of the nutrient content relative to conventional fertilizers, LPF also displayed significant improvements in crop yield, partial factor productivity, and agronomic efficiency by 33.56%, 200.01%, and 513.84%, respectively. These results indicate that LPF presents a promising solution for sustainable cassava cultivation.