Early prognosis of severe disease and preventive actions hang around as the mainstay in managing the novel SARS-COV-2 outbreak due to the lack of robust therapeutic strategies. Krebs von den Lungen-6 (KL-6 or KL-6/MUC1) is a relatively new discovered transmembrane mucoprotein that was shown to be a good predictor of disease severity in interstitial lung diseases (ILD). We aimed to systematically research the literature in order to assess the relationship between the KL-6 biomarker and prognosis of SARS-CoV-2 infection. A literature search was performed in PubMed, Embase, and Cochrane library databases from inception to 8 March 2021. After eligibility assessment, eight studies were finally included in the present systematic review. All included studies are observational and single-center. The data gathered suggests the importance of prognostic implications of KL-6 in COVID-19 as patients with a more severe disease had significantly higher levels of KL-6 at admission. Moreover, the KL-6 biomarker was associated with COVID-19 severity, lung lesion areas on computed tomography, pulmonary fibrosis, and coagulation disorders. The association with mortality is unclear and needs further research. More extensive trials are required to prove that facile, inexpensive, and good predictors of severe outcomes, such as KL-6, could be safely integrated into the clinical decision-making in patients with COVID-19.