Titanium matrix composites (TMCs) are the most attractive next-generation structural materials for lightweight design due to their high specific modulus and specific strength. Designing heterogeneous grain structures has been a widespread strategy for overcoming the strength-ductility trade-off in powder metallurgical TMCs. However, achieving a customizable heterogeneous grain structure in TMCs remains a formidable challenge. Here, we propose a novel interdiffusion and self-organization strategy based on the powder metallurgy method to fabricate a pelleted heterostructure Ti6Al4V(Ti64)–TiB composites, which integrates a heterogeneous distribution of reinforcements and heterogeneous grain structures of the matrix. The study reveals that the formation of the pelleted heterostructures is primarily governed by the interdiffusion reaction process between Ti and Al, and V elements, coupled with the growth and distribution changes of TiB induced by the interdiffusion reaction. Moreover, the pellet size is tailored by the spherical Ti–TiB composite powder, allowing precise control over the heterogeneous grain regions. This research contributes valuable insights into the manufacturing process of pelleted heterostructure Ti64–TiB composites and provides a conceptual framework applicable to the design of similar structures in various metal matrix composite systems.