Toxoplasmosis has long been recognized as a serious complication in immunocompromised host, particularly those with advanced HIV/AIDS, hematopoietic stem-cell transplantation (HSCT), solid-organ transplant (SOT), and hematological malignancies. The rapid expansion of targeted immunomodulators, including chimeric antigen receptor T-cell (CAR-T) therapies, monoclonal antibodies, and small-molecule inhibitors, is creating new at-risk populations beyond traditional transplant settings. We present a 9-year-old boy with high-risk B-cell acute lymphoblastic leukemia (B-ALL), who developed prolonged fever and macrophage activation syndrome (MAS). After an extensive unrevealing workup, disseminated acute toxoplasmosis was identified incidentally on bone marrow aspirate via morphologic identification of tachyzoites and confirmed by Toxoplasma gondii PCR. This case exemplifies the emerging threat of toxoplasmosis in non-transplant immunomodulated hosts and supports three core mitigation strategies. First, baseline Toxoplasma IgG and IgM serology should be obtained in all patients initiating targeted immunotherapy, recognizing that B-cell depletion or hypogammaglobulinemia may render IgG unreliable, and that IgM may be falsely negative, delayed, or persistently positive in immunocompromised individuals. Second, targeted PCR from clinically relevant compartments or metagenomic next-generation sequencing when conventional diagnostics is unrevealing should be applied early. Third, prevention requires a bundled approach: baseline screening, patient education for seronegative individuals, and trimethoprim-sulfamethoxazole prophylaxis with or without serial qPCR monitoring for seropositive patients. Toxoplasmosis is no longer a transplant-exclusive concern. As targeted immunomodulators reshape practice across rheumatology, oncology, neurology, and autoimmune disease, infectious diseases specialists must lead efforts to raise cross-specialty awareness, establish guidelines, and build registries to define the true burden of toxoplasmosis in these growing populations.