Periodontitis is a complex chronic inflammatory disease that is particularly associated with health-related conditions such as smoking, excessive drinking and depression. This research aimed to investigate the interaction between these lifestyles factors on periodontitis risk. This study included participants who participated in the National Health and Nutrition Examination Survey in the United States between 2009 and 2014. They had completed oral health-periodontal examination, Smoking-Cigarette Use Questionnaire, Alcohol Use Questionnaire, and Patient Health Questionnaire. Periodontal clinical attachment loss (CAL) of 3 mm or more and Patient Health Questionnaire-9 (PHQ-9) of 10 scores or more were used to identify periodontitis and depression, respectively. Daily alcohol consumption in the past year was classified into three levels: low (1 drink or less), moderate (between 1 and 3 drinks), and heavy drinking (4 drinks or more), while smoking was defined as having smoked at least 100 cigarettes in one's lifetime. Then, the logistic regression combined with interaction models were used to analyze the independent and combined effects of smoking, drinking and depression on periodontitis risk. The results indicated a statistically significant multiplicative interaction between smoking and depression in relation to the development of periodontitis, both in the overall population (P = 0.03) and among male participants (P = 0.03). Furthermore, among individuals experiencing depression, smoking was found to significantly increase the prevalence of periodontitis by 129% in the younger age group compared to non-smokers (odds ratio OR: 2.29; 95% confidence interval CI: 1.10 to 4.76). However, the interaction between smoking and alcohol consumption was only significant among females (P < 0.05). There was a dose-dependent relationship between drinking frequency and smoking on periodontitis prevalence. In the smoking population, occasional drinking (OR: 1.70; 95% CI: 1.22 to 2.37) and regular drinking (OR: 2.28; 95% CI: 1.68 to 3.11) significantly increased the prevalence of periodontitis compared to individuals without these two factors. These results suggested that there were interactive effects between smoking, drinking and depression on periodontitis risk and policies aimed at healthy behaviours and mental health may be beneficial for our oral health.