Background: Early recognition of hypoperfusion in suspected sepsis is essential. Laboratory pathways and the sampling site (arterial vs venous) influence timeliness and interpretability of biomarkers. Objective: To synthesize evidence on venous blood gas (VBG) and arterial blood gas (ABG)–derived indices, mainly lactate and veno-arterial CO₂ differences, for early detection and monitoring of sepsis, emphasizing practical laboratory implications. Methods: We undertook a structured review of user-provided sources: pathophysiology/review papers and clinical studies. We extracted study design, setting, and key quantitative findings relevant to early detection, agreement between VBG and ABG lactate, and venous-to-arterial CO₂ metrics. Results: Bedside lactate point-of-care testing shortens turnaround without clear mortality benefit. Peripheral venous lactate ≤2 mmol/L safely rule out arterial hyperlactatemia with high sensitivity, supporting venous screening and selective ABG confirmation. Agreement studies show strong arterial–venous correlations but wide limits of agreement, cautioning against simple conversion. CO₂-gap–based indices (Pv-aCO₂; Pcv-aCO₂/Ca-cvO₂) add prognostic/resuscitation context, though physiological caveats exist. Conclusions: For early detection, peripheral VBG lactate is an efficient screen; ABG is warranted when venous lactate >2 mmol/L or when precise gas exchange/acid-base data are needed. CO₂-gap indices can complement lactate to identify persistent hypoperfusion but require careful interpretation and standardized workflows.