Background Vitamin D may play a vital role in preventing the multi-system consequences of COVID-19 infections. The aim of this study is to evaluate the potential association between mean serum levels of vitamin D and COVID-19 and its correlation with severity and mortality. Results A case-control study conducted on 80 Egyptian patients admitted at Ain Shams University designated hospitals, Cairo, Egypt, from March 2021 to September 2021. Regarding the laboratory investigations, we found that COVID-19 cases have significantly lower lymphocytic counts than controls. Regarding vitamin D, this study showed a statistically significant positive correlation between vitamin D and lymphocytes, and there were statistically significant negative correlations between vitamin D, neutrophil-lymphocyte ratio, C-reactive protein, blood urea nitrogen, serum creatinine, aspartate aminotransferase, alanine aminotransferase, ferritin, lactate dehydrogenase, and D-dimer. Conclusion This study confirms that vitamin D deficiency is associated with the severity of COVID-19 clinically and laboratory.