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Malaria remains a major public health challenge in Africa, disproportionately affecting vulnerable populations, especially immunocompromised groups such as individuals living with HIV/AIDS, malnourished children, and patients undergoing immunosuppressive therapies. These populations are at increased risk of malaria infection, experience more severe disease manifestations, and face poorer treatment outcomes due to compromised immune function. Despite significant advances in malaria control, existing prevention strategies often do not adequately address the unique needs of immunocompromised individuals. This review explores the pathophysiological interplay between malaria and immunosuppression, highlighting how immune deficits exacerbate susceptibility and severity of malaria infections. Current malaria prevention measures—including vector control, chemoprophylaxis, and health education—are assessed with a focus on their applicability and limitations in immunocompromised populations. Key barriers such as health system fragmentation, socio-economic constraints, and emerging insecticide and drug resistance are identified as critical challenges that undermine prevention efforts. To reduce the disproportionate malaria burden in immunocompromised groups, the review advocates for integrated healthcare services, targeted vector control, expanded prophylactic interventions, and enhanced community engagement. Strengthening research and surveillance will inform tailored, evidence-based policies. Ultimately, a comprehensive and collaborative public health approach is essential to safeguard the health of Africa’s most vulnerable populations and accelerate progress toward malaria elimination. Peer Review History: Received 1 December 2025; Reviewed 12 January 2026; Accepted 17 February; Available online 15 March 2026 Academic Editor: Prof. Cyprian Ogbonna ONYEJI, Obafemi Awolowo University, Ile-Ife, Nigeria, conyeji@oauife.edu.ng Reviewers: Noha El Baghdady, MTI University, Cairo, Egypt, nohasalah21@yahoo.com Prof. Gorkem Dulger, Duzce University, Turkey, gorkemdulger@yandex.com