In intensive care units, sepsis is the first cause of death. In this pathology, inflammation and oxidative status play a crucial role in patient outcomes. Interestingly, 92% of septic patients exhibit low selenium plasma concentrations (a component of antioxidant enzymes). Moreover, Spirulina platensis, a blue-green algae, demonstrated anti-inflammatory effects. In this context, the main purpose of our study was to analyze the effect of a selenium-enriched spirulina after a selenium deficiency on sepsis outcome in rats. Sixty-four rats were fed 12 weeks with a selenium-deficient food. After 8 weeks, rats were supplemented (via drinking water) for 4 weeks with sodium selenite (Se), spirulina (Spi), or selenium-enriched spirulina (SeSp). Sepsis was then induced by cecal ligature and puncture, and survival duration was observed. The plasma selenium concentration was measured by ICPMS. Expression of GPx1 and GPx3 mRNA was measured by RT-PCR. Blood parameters (lactates and HCO3− concentrations, pH, PO2, and PCO2) were analyzed at 0, 1, and 2 h as well as inflammatory cytokines (IL-6, TNF-α, IL-10). Sodium selenite and SeSP supplementations restored plasma selenium concentration prior to sepsis. The survival duration of SeSP septic rats was significantly lower than that of selenium-supplemented ones. Gpx1 mRNA was increased after a selenium-enriched spirulina supplementation while Gpx3 mRNA levels remained unchanged. Furthermore, sodium selenite prevented sepsis-induced acidosis. Our results show that on a basis of a Se deficiency, selenium-enriched spirulina supplementations significantly worsen sepsis outcome when compared to Se supplementation. Furthermore, Se supplementation but not selenium-enriched spirulina supplementation decreased inflammation and restored acid–base equilibrium after a sepsis induction.