Key modifiable risk behaviors such as smoking, poor diet and physical inactivity often cluster and may have multiplicative adverse effects on health. This study investigated barriers and facilitators to healthy eating and physical activity (PA) in overweight Mexican-origin smokers to inform the adaptation of an evidence-based smoking cessation program into a multiple health behavior change intervention. Five focus groups were conducted with overweight Mexican-origin men (n = 9) and women (n = 21) who smoked. Barriers and facilitators of healthy eating and PA were identified, and gender differences were assessed. Participants expressed some motivation to eat healthfully and identified strategies for doing so, yet many women experienced difficulties related to personal, family and work-related circumstances. Barriers to healthy eating among men were related to food preferences and lack of familiarity with fruits and vegetables. Participants performed PA primarily within the context of work and domestic responsibilities. Stress/depressed mood, lack of motivation and concern for physical well-being limited further PA engagement. Routines involving eating, PA and smoking highlight how these behaviors may be intertwined. Findings emphasize the importance of social, structural and cultural contexts and call for additional investigation into how to integrate healthy eating and PA into smoking cessation interventions for overweight Mexican-origin smokers.