Introduction: Currently pulmonary fibrosis in post-COVID individuals represents a crucial milieu of investigation due to long-term associated complications and worse clinical outcome. Lack of studies in Indian population confers a crucial need for elucidating possible targets and mechanisms to explore better management and outcome. Hence, this study aimed to explore the role of circulating miRNA-21 in patients from South India after COVID-19 recovery, while targeting TGF-ß signaling pathway involved in the development of pulmonary fibrosis. Methods: This prospective, single centre, hospital-based study enrolled a total of 50 participants in the age group of 50 to 60 years including 25 non-infected controls and 25 patients who were recovered after 3-6 months of COVID-19 infection and presented radiological pulmonary abnormalities. Quantification of miRNA-21 and selected gene transcripts (TGF-ß, Col1A2, Col3A1, and α-SMA) was performed in plasma samples of both patients and controls. Results: Significantly increased expression levels of miRNA-21 was observed in patient samples compared to controls (4.50 ± 1.03 vs 12.60 ± 3.52, p < 0.0001) with 72.10% sensitivity and 80.10% specificity. Further, significantly increased levels of central fibrosis regulatory gene transcript TGF-ß (0.56 ± 0.27 vs 1.83 ± 0.98), two crucial collagen transcripts Col1A2 (0.62 ± 0.19 vs 1.56 ± 1.00) and Col3A1 (0.61 ± 0.27 vs 1.54 ± 0.89), and α-SMA (0.46 ± 0.17 vs 1.20 ± 0.78) was observed in patients compared to controls. Western-blot analysis also showed almost similar observations at proteins levels. Conclusion: Circulating miRNA-21 may provide crucial insights for elucidating TGF-ß mediated pulmonary remodeling involved in the fibrosis development and achieve better clinical outcome for post-COVID patients after recovery, in real-time with high diagnostic accuracy.