An abundant literature in the field of sepsis focuses on the role of NO. Inhibiting NO synthesis corrects certain hemodynamic parameters of septic shock but failed to improve outcome in patients. Conversely, administration of NO donors lowers blood pressure but restores microcirculatory flow in patients with sepsis. We undertook a systematic review of the literature to comprehensively summarize the results of studies exploring the effects of systemic NO donors in sepsis. We included both clinical and preclinical data. We described the details surrounding NO donor administration, and the results obtained in each study were regrouped in broad categories. In the case of animal research, we limited our data collection to in vivo protocols and described the sepsis model. Finally, we critically appraised all the studies included in the review. Overall, the reviewed publications aimed for physiopathological description rather than clinical relevance and did not meet the required criteria for extrapolation to clinical practice. With this reserve, NO donors usually improved the outcomes measured (e.g., mortality, pulmonary hypertension, tissue/organ perfusion, etc.) but also lowered blood pressure. We conclude that our findings warrant further animal experimentation designed to maximize clinical relevance.