Recent research has increasingly highlighted the adaptive characteristics of the innate immune system, revealing its capacity for a heterologous memory of previous infections. Allergen-specific immunotherapy (AIT) has demonstrated that innate immune cells, such as monocytes, macrophages, and natural killer (NK) cells, can provide protection against specific diseases even in the absence of lymphocyte support. The mechanisms underlying innate host defense and the immunological memory of adaptive immunity differ significantly in terms of cellular populations and molecular pathways. Prototypical innate immune cells, including NK cells and monocytes/macrophages, contribute to the sustained heightened state of innate immunity known as “trained immunity,” which enhances resistance to secondary infections. Trained immunity is typically initiated through the engagement of pattern recognition receptors (PRRs) by microbial structures, suggesting that vaccines designed to induce trained immunity should incorporate appropriate PRR ligands. This approach not only offers protection against reinfection in a manner independent of T and B cells but also promotes nonspecific epigenetic reprogramming that enhances immune responses. For instance, Bacillus Calmette-Guérin (BCG) vaccination has been linked to long-lasting immune modifications associated with a non-specific immune response to various infections, characterized by heterologous T helper 1 (Th1) and Th17 responses. Emerging evidence indicates that heat-killed Mycobacterium manresensis can induce trained immunity in vitro, although its effectiveness in vivo remains to be fully established. This highlights the potential of novel strategies in vaccine development, particularly through the lens of trained immunity. The concept of trained immunity-based vaccines (TIbV) presents a paradigm shift in immunization strategies, as these vaccines can elicit broad-spectrum protection against a variety of pathogens. By leveraging the principles of trained immunity, TIbV can enhance both innate and adaptive immune responses, potentially improving the efficacy of conventional vaccines and offering new avenues for immunotherapy. The integration of trained innate immunity into vaccine development holds significant promise for enhancing immune protection against infectious diseases. By harnessing the principles of trained immunity, these innovative vaccines can enhance innate immune responses, potentially improving protection against a wide range of infectious diseases and contributing to better public health outcomes.