Novel coronavirus disease (COVID-19) has affected nearly 7 million individuals and claimed more than 0.4 million lives to date. There are several reports of gender differences related to infection and death due to COVID-19. This raises important questions such as “Whether there are differences based on gender in risk and severity of infection or mortality rate?” and “What are the biological explanation and mechanisms underlying these differences?” Emerging evidence has proposed sex-based immunological, genetic, and hormonal differences to explain this ambiguity. Besides biological differences, women have also faced social inequities and economic hardships due to this pandemic. Several recent studies have shown that independent of age males are at higher risk for severity and mortality in COVID-19 patients. Although susceptibility to SARS-CoV-2 was found to be similar across both genders in several disease cohorts, a disproportionate death ratio in men can be partly explained by the higher burden of pre-existing diseases and occupational exposures among men. From an immunological point of view, females can engage a more active immune response, which may protect them and counter infectious diseases as compared to men. This attribute of better immune responses towards pathogens is thought to be due to high estrogen levels in females. Here we review the current knowledge about sex differences in susceptibility, the severity of infection and mortality, host immune responses, and the role of sex hormones in COVID-19 disease.