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Background: Rheumatic and autoimmune diseases share key pathogenic mechanisms including chronic inflammation, oxidative stress, microvascular dysfunction, mitochondrial impairment, and persistent pain or fatigue. These processes underlie a broad spectrum of conditions managed in rheumatology, ranging from inflammatory and degenerative joint diseases to chronic pain syndromes and selected infectious complications. Medical ozone, administered at low and controlled doses using certified medical protocols, induces a mild oxidative stimulus that activates endogenous antioxidant and cytoprotective pathways. Methods: This narrative review integrates mechanistic, translational, and clinical evidence on medical ozone therapy derived from foundational experimental studies and a structured search of PubMed and Scopus databases (2000–2025), focusing on conditions relevant to rheumatologic practice. Results: Medical ozone primarily modulates redox homeostasis through activation of the Nrf2/heme oxygenase-1 pathway, with downstream effects on inflammatory signalling, endothelial function, microcirculation, mitochondrial metabolism, and neuroimmune regulation. Adjunctive clinical evidence supports its use in rheumatoid arthritis, systemic sclerosis–related vasculopathy, knee osteoarthritis, fibromyalgia, and myalgic encephalomyelitis/chronic fatigue syndrome. Robust data support ozone therapy in discogenic low back pain, while its role in inflammatory spondyloarthropathies appears limited to symptomatic management. Emerging evidence also suggests a potential adjunctive role in treatment-related toxicities and selected joint or ulcer-related infections. Conclusions: Medical ozone shows mechanistic plausibility and converging clinical signals as an adjunctive intervention in selected rheumatologic conditions. However, heterogeneity of protocols and limited high-quality trials preclude routine clinical implementation, highlighting the need for well-designed multicentre randomised studies.