Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to have higher pathogenicity among patients with obesity. Obesity, termed as body mass index greater than 30 kg/m(2), has now been demonstrated to be important comorbidity for disease severity during coronavirus disease 2019 (COVID-19) pandemic and associated with adverse events. Unraveling mechanisms behind this phenomenon can assist scientists, clinicians, and policymakers in responding appropriately to the COVID-19 pandemic. In this review, we systemically delineated the potential mechanistic links between obesity and worsening COVID-19 from altered physiology, underlying diseases, metabolism, immunity, cytokine storm, and thrombosis. Problematic ventilation caused by obesity and preexisting medical disorders exacerbate organ dysfunction for patients with obesity. Chronic metabolic disorders, including dyslipidemia, hyperglycemia, vitamin D deficiency, and polymorphisms of metabolism-related genes in obesity, probably aid SARS-CoV-2 intrusion and impair antiviral responses. Obesity-induced inadequate antiviral immunity (interferon, natural killer cells, invariant natural killer T cell, dendritic cell, T cells, B cell) at the early stage of SARS-CoV-2 infection leads to delayed viral elimination, increased viral load, and expedited viral mutation. Cytokine storm, with the defective antiviral immunity, probably contributes to tissue damage and pathological progression, resulting in severe symptoms and poor prognosis. The prothrombotic state, driven in large part by endothelial dysfunction, platelet hyperactivation, hypercoagulability, and impaired fibrinolysis in obesity, also increases the risk of severe COVID-19. These mechanisms in the susceptibility to severe condition also open the possibility for host-directed therapies in population with obesity. By bridging work done in these fields, researchers can gain a holistic view of the paths forward and therapeutic opportunities to break the vicious cycle of obesity and its devastating complications in the next emerging pandemic.