Sickle cell disease (SCD) is characterized by recurrent vaso-occlusive crisis (VOC). Patients with SCD have impaired immunity and are thus predispose to infections. The vast majority of SCD patients live in underdeveloped nations with high prevalence and transmission rates of infections. This makes the SCD patients prone to infections, which frequently precipitate VOC. We reviewed the role of infection in the pathogenesis of VOC, taking into consideration all potential mechanisms from previous studies and hypothetical perspectives. The potential mechanisms through which infections may lead to VOC involve several pathological changes including pneumonitis, pyrexia, acute phase reaction, hypercoagulability, neutrophilia, eosinophilia, thrombocytosis, bronchospasm, red cell cytopathic and membrane changes, auto-antibodies mediated red cell agglutination and opsonization, diarrhoea and vomiting, which may act singly or in concert to cause red cell sickling. These changes can induce sickling directly or indirectly through their adverse effects on Hb oxygenation and polymerization, hydration, blood viscosity, red cell metabolism, procoagulant activation, intercellular adherence and aggregation, culminating in VOC. There is therefore the need to ameliorate the burden of infection on SCD through immunization, prophylactic and therapeutic use of antimicrobials, barrier protection and vector control in communities with high prevalence of SCD.