Introduction As a homologue of the angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2) has been identified as the main receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invasion. We aimed to investigate the role of serum ACE in predicting the coronavirus disease 2019 (COVID-19) disease progression and the underlying mechanisms. Methods We retrospectively enrolled 120 patients with confirmed COVID-19 who underwent serum ACE detection on admission. The clinical characteristics and laboratory findings during hospitalization were evaluated dynamically to identify the potential risk factors for disease progression. Results ACE level was demonstrated as one of the independent risk factors. Patients with ACE level <= 33.5 U/L showed a higher cumulative virus RNA detection rate, elevated pro-inflammatory mediators levels, declined lymphocyte count, and decreased SARS-CoV-2-specific antibodies than those with ACE level > 33.5 U/L. Conclusion Lower serum ACE levels in relation to delayed virus elimination, hyperinflammatory condition, and impaired host antiviral immune responses contribute to disease progression of COVID-19.