Although several studies have reported the multiple systemic effects of betel nut (BN) chewing, analyses performed on the colonic system have been few. To analyze the association between BN chewing and diverticulosis, we conducted a cross-sectional study of 5,586 eligible participants who underwent colonoscopy at a medical center in Taiwan from 2010 to 2016. BN chewing was recorded based on an assessment of personal history. Diverticulosis was categorized based on whether colonoscopies had been performed during health examinations by trained physicians at Tri-Service General Hospital. The association between different exposures, including cigarette, alcohol, BN, and diverticulosis, was also analyzed. Our study included 3,161 males and 2,425 females, and males have significantly higher prevalence rates of BN chewing than females (11.1% versus 0.3%, respectively). In the male group, BN chewing had an adjusted odd ratio (OR): 1.65(95% confident interval (CI): 1.12–2.44) with the presence of diverticulosis. Among the combination of exposures of cigarette, alcohol, and BN, the group with BN chewing combined with smoking and drinking showed significant association between diverticulosis with adjusted OR: 1.909 (95% CI, 1.188–3.065). Further subgroup analysis displayed adjusted OR: 2.310 (95% CI, 1.245–4.287) in obesity and OR: 2.406 (95% CI, 1.205–4.803) in elderly male. Thus, BN chewing is independently associated with diverticulosis in male.