Background: Coronavirus disease 2019 (COVID-19) is an emerging zoonotic disease caused by the new respiratory virus SARS-CoV2. It has a tropism in the lung tissues where excess target receptors exist. Periostin plays a role in subepithelial fibrosis associated with bronchial asthma. Since the Coronavirus's target is the human respiratory system, Periostin has been recently described as a valuable new biomarker in the diagnosis and evaluation of disease in patients with COVID-19 lung involvement. Objectives: To assess the level of Periostin in the serum of COVID-19 patients and to correlate its role in disease severity and prognosis. Subjects and Methods: Periostin serum levels were measured for 63 patients attending three main COVID-19 Control Centers in Baghdad, compared to 25 healthy subjects, using an enzyme-linked immunosorbent assay (ELISA) from January 2021 to April 2022. Results: Serum levels of Periostin among studied groups with (mild - moderate, severe - critical, post-COVID, and controls) were (17.3, 664, 597, and 48) ng/dl respectively. The serum concentration of Periostin was highly significant in (severe- critical and post-COVID) than in other groups. Conclusions: The elevated level of serum Periostin in COVID-19 patients correlated with disease severity and post-COVID lung complications. The high Periostin level is consistent with high inflammatory markers, which might be used as an indicator of COVID-19 severity and predict a bad prognosis.