Background: SARS-CoV-2, originally described as a respiratory pathogen, has been identified as a multisystem disease with complex and interconnected pathophysiological processes. Methods: The PRISMA framework was used to systematically review the evidence and identify and synthesize it in PubMed, Scopus and Web of Science between January 2020 and December 2025. Of the 1,410 screened records, 147 peer-reviewed studies involving more than 2 million patients were included. The frequency of organ involvement, important biomarkers and long-term outcomes were derived and the quality of the studies was assessed using standardized tools. Results: The quantitative synthesis showed that 78 % of hospitalized patients had pulmonary involvement, 32 % cardiovascular, 43 % neurological and 28 % renal, with 10–35 % showing persistent organ dysfunction at 6 months post-infection. The most common were cytokine storm (IL-6 >100 pg/mL in 72% of severe cases), endothelial dysfunction (biomarkers elevated in 87% of patients) and microvascular thrombosis (D-dimer >2000 ng/mL in 46% of patients). Most domains were scored as having moderate-to-high confidence in quality assessment. Conclusions: COVID-19 has long-term, multi-organ sequelae that require integrated multidisciplinary management. Healthcare systems should be ready to participate in long-term monitoring, rehabilitation and special therapeutic development. The results offer a strong evidence base for clinical practice and post-pandemic health policy.