Background: COVID-19 may trigger the progression of atherosclerosis, potentially leading to its clinical manifestation. Among the serum biomarkers related to atherosclerotic disease, it seems helpful to evaluate biochemical factors such as CD147, ACE2, and ACE in patients with COVID-19. Methods: In this case-control study, serum samples from 90 patients were analyzed. The cohort included 30 patients hospitalized in the intensive care unit with COVID-19, 30 patients hospitalized in the ward with COVID-19, and 30 healthy individuals from Ayatollah Kashani Hospital (Tehran, Iran). These patients were admitted between December 10, 2022, and March 10, 2023. The concentrations of cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and the activity levels of angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), troponin, CPK, CPK-MB, and CD147 were determined and analyzed among the three groups. Results: There was no significant difference in age between the patients (55.40 ± 10.34 years) and the control group (58.34 ± 11.71 years). SARS-CoV2 viral RNA was detected in the pharyngeal swab samples of the COVID-19 patients. The levels of CD-147 (2528.43 ± 12.43 vs. 2176.7 ± 9.87 vs. 1346.3 ± 14.23), ACE (83 ± 3.05 vs. 97 ± 1.55 vs. 30.1 ± 2.32), troponin (0.972 ± 0.25 vs. 0.784 ± 0.21 vs. 0.021 ± 0.68), and cholesterol (199.73 ± 2.43 vs. 175.87 ± 5.21 vs. 144.97 ± 8.74) were significantly higher in severe cases compared to non-severe cases (P < 0.05). ACE (AUC = 0.894) and CD147 (AUC = 0.821) had the highest sensitivity and specificity among the studied factors, respectively. Patients with normal levels of ACE and CPK-MB had a 0.16 times lower and 4.37 times greater chance of experiencing severe disease, respectively. Three strong correlations were found among the studied parameters: CD147 with ACE2 (r = 0.721) and cholesterol with triglyceride (r = 0.602) (P < 0.05). Conclusions: Examining ACE and CD147 can help determine a person's susceptibility to atherosclerosis. These two factors have greater sensitivity and specificity and could be used as potential markers for monitoring disease progression.