Background: Chlorine dioxide (ClO
2), formulated as an aqueous solution (CDS), has been proposed as a therapeutic agent, yet its classification among oxidizing compounds is frequently confounded with chemically distinct species—sodium chlorite (NaClO
2) and sodium hypochlorite (NaOCl). Objective: This study aimed to synthesize the physicochemical, mechanistic and cellular basis of ClO
2 action and to delineate the distinctions between ClO
2 and related oxidants, with explicit separation of established data from hypothesized data. Methods: The methodology includes a narrative synthesis of electrochemical data, primary toxicological and clinical literature (PubMed) and the redox-biology literature on low-dose oxidant signaling. Results: ClO
2 is a neutral free radical that acts via one-electron transfer (E°′ = +0.95 V vs. SHE for the half-reaction ClO
2 + e
− → ClO
2−, essentially pH-independent over pH 4–8, pH-independent) without chlorination. Its antimicrobial action is attributable to oxidation of thiol-dependent enzymes and membrane constituents and to the inhibition of bacterial respiratory metabolism; host-cell sparing is consistent with differential glutathione-dependent buffering. Controlled human ingestion studies at low concentrations report a favorable short-term safety profile; conversely, the principal metabolite (chlorite) is associated with documented developmental toxicity in animals and regulatory caution by EPA/WHO. Low-dose ClO
2 exposure is hypothesized—but not yet directly demonstrated—to elicit dose-dependent adaptive redox responses and redox-regulatory modulation. Conclusions: The one-electron, non-chlorinating chemistry of ClO
2 provides a coherent mechanistic framework. The translation of this framework into clinical application requires prospective trials and direct mechanistic measurement, ideally conducted by independent investigators. The following mechanisms are hypothesized and have not yet been directly demonstrated in vivo: modulation of oxidative phosphorylation, mitochondrial oxygenation, and associated redox-regulatory signaling. Reported antimicrobial efficacy typically occurs in the low-ppm range (0.1–5 ppm), whereas adverse effects on mammalian cells in the reviewed literature are reported at concentrations at least one order of magnitude higher; direct head-to-head cytotoxicity comparisons remain scarce and are identified as a priority for future work. This differential thiol buffering—in particular, the higher glutathione content of many mammalian cells relative to many pathogens—has been proposed as a contributing basis for host-cell sparing; direct quantitative confirmation in vivo is not yet available. Bacterial species possess their own thiol-based defense systems (e.g., mycothiol in actinomycetes, bacillithiol in Firmicutes), and the interplay between ClO
2 and these systems requires further investigation.