Sickle cell disease (SCD), a genetic hemoglobin disorder, is a major public health challenge in sub-Saharan Africa, particularly in Tanzania, due to its association with high morbidity and mortality from infections. The disease is the leading cause of complications, emphasizing the urgent need for effective preventive strategies and diagnostic protocols. We evaluated the implementation and effectiveness of infection prevention measures and laboratory diagnostic compliance at Nyamagana District Hospital, emphasizing their effects on patient outcomes and survival rates. This retrospective observational study analyzed the medical records of 157 patients with SCD admitted to Nyamagana District Hospital for infection treatment between January 2022 and 2024. The infection profiles, utilization of preventive interventions (recommended drugs, vaccinations, and chemoprophylaxis), and diagnostic laboratory compliance were assessed. Of the 157 participants, 90.4% had at least one infection during their hospital stay, suggesting the vulnerability of this population to infections. Furthermore, malaria emerged as the most prevalent type of infection (40.1%), which is consistent with its endemic status in Tanzania. Other significant infections included unspecified diarrhea (12.5%) and upper respiratory tract infections (10.8%). Despite the high coverage rates of penicillin V prophylaxis (72%) and pneumococcal vaccination (100%), the utilization of malaria chemoprophylaxis and hydroxyurea was low (only 10.8% and 16.6%, respectively). The diagnostic laboratory test compliance, essential for accurate infection management, was moderate at 63.1%, with significant deficiencies in the blood, urine, and stool cultures and antibiotic susceptibility testing. The administration of hydroxyurea significantly reduced malaria prevalence (P=0.005), fewer vaso-occlusive crises (P<0.001), and severe anemia incidence (P=0.034). Thus, enhancing access to preventive measures and improving diagnostic laboratory compliance are crucial steps for reducing infection-related complications among patients with SCD in Nyamagana.