Infections leading to sepsis cause substantial pediatric hospitalizations and deaths worldwide, and healthcare management is particularly difficult in highest-burden low-income settings such as Mali due to conflicting evidence of treatment effectiveness and mounting antibiotic resistance. Few studies describe region-specific burden of sepsis and sepsis management. We aimed to (i) describe the burden of hospitalizations and deaths and (ii) assess the impact of supportive care therapies on in-hospital mortality among patients with sepsis at l’Hôpital Gabriel Touré (HGT), a tertiary care center in Bamako, Mali and (iii) evaluate the health impact and economic feasibility of an endotoxin vaccine if implemented in Bamako. We used a prospective cohort study to temporally describe etiology and case fatality of bacterial infections at HGT. Multivariable logistic and Cox regression models were used to evaluate associations between supportive care therapies (antibiotics, fluids, and oxygen therapy) and in-hospital death. We estimated the health impact and economic feasibility of endotoxin vaccine (maternal, pediatric after birth, and joint scenarios) if implemented in Bamako. Vaccine-preventable infection burden remains low at HGT, while proportions of patients with S. aureus and Gram-negative rods (GNR) and associated mortality have increased. No impact of antibiotics on mortality [adjusted odds ratio (aOR: 1.40, 95% confidence interval (CI): 0.90, 2.18) or fluids (aOR: 1.27, 95% CI: 0.97, 1.65) was found, while supplemental oxygen was associated with increased odds of in-hospital death (aOR: 2.09, 95% CI: 1.50, 2.91). A maternal vaccination program was estimated to avert 569 disability-adjusted life years (DALYs) per birth cohort (95% CI: 243, 880), costing $127 per DALY averted (95% CI: $81, $301), and was the most cost-effective vaccine scenario. In-hospital mortality due to infections leading to sepsis has drastically risen and remains alarmingly high. Given no apparent benefit of current supportive therapies utilized, further study is needed to improve sepsis management and critical care. If efficacious endotoxin vaccine were licensed and administered maternally, it would be lifesaving and cost-effective if implemented.