Objective The aim of this study was to identify an association between the severity of COVID-19 in obese-diabetic patients and altered serum levels of MMP-7, MMP-9, TGF-β, and PDGF macrophage activation markers. Methodology The study included 70 COVID-19 patients, divided into two groups: Group 1 included: Obese COVID-19 patients with type 2 diabetes mellitus (T2D, n=22 patients) and group 2 included; non-obese, non-diabetic COVID-19 patients as an age- and sex-matched control group (n=48 patients). Serum levels of the tested biomarkers were measured by ELISA at admission and after one weak follow-up. Results There was a significant reduction in the serum levels of LBP in obese-diabetic COVID-19 patients versus the control group (8.34±3.94 vs 20.78±7.61) (p 0.0001). Significant elevation of MMP-7, MMP-9, PDGF and TGF-β was detected in obese diabetic COVID-19 patients compared to the non-obese non-diabetic group: 1044.7±519.6 vs 405.6±164.1, 483.05±46.5 vs 173.31±76.26, 154.5±62.78 vs 39.77±21.52, and 603.05±258.82 vs 180.29±97.17, respectively. The serum levels of macrophage activation markers in obese-diabetic patients one week after admission revealed that patients with acute respiratory distress syndrome (ARDS) had significantly higher serum levels of MMP-7 and MMP-9 than non-ARDS patients (p 0.02 and p 0.01 respectively). Conclusion Macrophages were mainly polarized towards the M2 phenotype in obese-diabetic COVID-19 patients with significant upregulation of the pro-fibrotic markers MMP-7, MMP-9, PDGF, and TGF-β. Thus, high levels of MMP-7 and MMP-9 are associated with ARDS in severe COVID-19 disease among obese-diabetic patients.