Background/Objectives: Post-COVID-19 pulmonary fibrosis (PCPF) and idiopathic pul-monary fibrosis (IPF) show clinical parallels, suggesting overlapping pathogenesis. This study investigated the dysregulation of key proteases, matrix metalloproteinases-2 and -9 (MMP-2/9), and associated inflammatory and endothelial markers in both conditions. Methods: We analyzed MMP-2 and MMP-9 gene expression in peripheral blood leuko-cytes and corresponding plasma protein levels in patients 6 and 12 months after SARS-CoV-2 infection, stratified by the presence (FB+) or absence (FB-) of post-COVID pulmonary fibrosis. These groups were compared to IPF patients and pre-pandemic healthy controls. Results: Results showed a significant, sustained increase in MMP-2/9 in post-COVID patients versus controls, which was most pronounced in the PCPF group and mirrored the dysregulation in IPF. This proteolytic shift corresponded to a distinct sys-temic profile: patients without fibrosis showed reduced levels of acute-phase cytokines (TNF-α, IL-6), whereas patients with fibrosis exhibited both elevated cytokines and in-creased markers of endothelial dysfunction (Endothelin-1, sICAM-1). Conclusions: The findings demonstrate that sustained MMP-2/9 overexpression is a hallmark of post-COVID fibrosis and is associated with a transition from systemic inflammation to chronic endothelial impairment. The convergence of this molecular profile in PCPF and IPF indicates shared pathophysiological pathways driving fibrosis. This positions MMP-2 and MMP-9 as promising biomarkers and potential therapeutic targets for mitigating progressive fibrotic lung disease.