Background A paradoxical hypothesis about the effect of smoking on patients infected with severe acute respiratory syndrom 2 (SARS-CoV-2) infection still exists. Furthermore, gender-discrepancy in the impact of smoking on COVID-19 severity was given little attention. Thus, the aims of the present study were to evaluate the prevalence of smoking and the COVID-19 infection severity in a sample of adult patients diagnosed with COVID-19 and to explore the relationship between smoking status and SARS-CoV-2 infection severity in the overall sample and stratified by gender. Methods A retrospective analytical study was conducted on patients diagnosed with COVID-19 cases between December, 2020 and April, 2021 from three leading laboratories in Lebanon. Sociodemographic characteristics, smoking status and clinical symptoms were collected. Multinomial logistic regression analysis was used to explore the relationship between smoking status and SARS-CoV-2 infection severity. Results A total of 901 confirmed COVID-19 cases participated in the study, 50.8% were females. The mean age of patients was 38.4 years (SD = 15.3). Of the total sample, 521(57.8%) were current smokers. Regarding infection severity, 14.8% were asymptomatic, 69.9% had mild symptoms, while 15.3% had severe infection. In the overall sample, smoking status, smoking types and dose–response were not significantly associated with infection severity. Upon stratifying the entire sample by gender, no association was found between all the considered variables with infection severity among females. However, a significant association was found among male with mild infection compared to their asymptomatic counterparts (OR = 1.78 95% CI (1.01–3.13)). Waterpipe smoking was found to be associated with infection severity among male with mild infection (OR 2.64 (95% CI 1.32–5.27)) and severe infection 2.79, 95% CI (1.19–6.53) compared to their asymptomatic counterparts. Conclusion Our fundings highlight sex differences in the association between tobacco smoking and COVID-19 severity. Current tobacco smoking was not associated with SARS-CoV-2 infection severity among female patients, however, tobacco smoking, particularly waterpipe, was found to be associated with infection severity among male. Thus, the battle against smoking should continue by assisting smokers to successfully and permanently quit.