Background: The Comrades Marathon is the world’s oldest and largest ultra-marathon, held annually between Durban and Pietermaritzburg, South Africa, since 1921. As a nationally televised event with substantial participation, it provides a unique natural laboratory for studying the physiological demands of prolonged, high-intensity endurance running. This narrative review synthesizes current evidence on physiological responses, performance trends, and health implications associated with participation in the Comrades Marathon. Methods: A systematic search of EBSCO, PubMed, SciELO, and Web of Science identified studies published up to December 2025. Of 116 records retrieved, 42 publications (field studies and case reports) met eligibility criteria and focused specifically on the Comrades Marathon. Results: Women represented 4.2% of finishers, with female participation beginning in 1975. Growth in finishers during the 1970s was driven primarily by men aged 30–59 years. Men were consistently faster than women across all age groups, although the sex performance gap narrowed over time and overall performance improved. Peak performance occurred at ⁓29.9 years in men and ⁓36.0 years in women. Medical encounters occurred at rates up to 20 per 1000 starters. The most affected organ systems were fluid/electrolyte (8.8%; 8.3–9.4), central nervous system (4.0%; 3.7–4.5), and gastrointestinal (2.9%; 2.6–3.2). Dehydration (7.5%; 7.0–8.1) and exercise-associated muscle cramping (3.2%; 2.9–3.6) were the most common diagnoses. Exercise-associated hyponatremia was uncommon (<2%), whereas hypernatremia was substantially more prevalent. Early race editions reported isolated deaths, likely due to ischemic heart disease. Cardiac biomarker elevations and echocardiographic changes observed post-race were transient. The race induced muscle inflammation without major knee MRI abnormalities. In the 1970s, cases of acute kidney injury and renal failure occasionally required dialysis. Faster, well-trained runners showed higher rates of post-race upper respiratory tract infection than slower, less-trained runners. Conclusions: Participation in the Comrades Marathon is associated with well-characterized post-race physiological disturbances. Notably, the event demonstrates an unusually high prevalence of acute kidney injury and hypernatremia compared with other ultra-endurance races, underscoring the substantial renal and fluid–electrolyte stress imposed by prolonged, high-intensity running in challenging environmental conditions. These insights can inform individualized hydration strategies, targeted race preparation, and optimized medical support for ultra-endurance athletes.