This study investigates the potent induction of trained immunity by a high-complexity blend of two β-glucans derived from *Saccharomyces cerevisiae*. The β-glucans, specifically ABB i16, were found to significantly enhance the trained innate immune response in human primary monocytes, leading to a robust secondary response upon an unrelated challenge. The induction of trained immunity required the activation of multiple receptors and downstream signaling molecules, including Dectin-1/CR3, TLR4, and MMR, as well as Raf-1, Syk, and PI3K. In *in vivo* murine models of melanoma and bladder cell carcinoma, pre-treatment with the β-glucan preparation significantly reduced tumor growth. These findings suggest that the β-glucans from *S. cerevisiae* have the potential to induce effective trained immunity and could contribute to the development of novel therapies for infections and cancer.This study investigates the potent induction of trained immunity by a high-complexity blend of two β-glucans derived from *Saccharomyces cerevisiae*. The β-glucans, specifically ABB i16, were found to significantly enhance the trained innate immune response in human primary monocytes, leading to a robust secondary response upon an unrelated challenge. The induction of trained immunity required the activation of multiple receptors and downstream signaling molecules, including Dectin-1/CR3, TLR4, and MMR, as well as Raf-1, Syk, and PI3K. In *in vivo* murine models of melanoma and bladder cell carcinoma, pre-treatment with the β-glucan preparation significantly reduced tumor growth. These findings suggest that the β-glucans from *S. cerevisiae* have the potential to induce effective trained immunity and could contribute to the development of novel therapies for infections and cancer.