Background: Tobacco use remains a leading cause of preventable death among older adults, but few studies have examined social isolation as a risk factor for smoking in US. older adults. Methods: Using National Health and Aging Trends Study (NHATS) data, we conducted multivariate analyses of smoking in a sample of 8136 adults ages 65 and older. Results: Social isolation and severe isolation were associated with higher odds of smoking (OR: 2.48 and 5.48, p = 0.002 and p < 0.001). Individuals with mild (OR: 1.46, p = 0.006), moderate (OR: 1.80, p = 0.001), or severe (OR: 3.05, p = 0.001) symptoms of depression/anxiety also had higher odds of smoking. Conclusions: Social isolation is a significant risk factor for smoking in US older adults. Further research is needed to support the development of interventions to reduce social isolation and smoking behavior in older adults.