This study aimed to assess changes in learned self-regulatory skills and barriers self-efficacy associated with theory-based behavioral weight-loss treatments with different curricular emphases, and to evaluate mechanisms of short- and long-term changes in exercise and eating behaviors via self-regulatory skills usage to inform theory and improve lagging intervention effects. Women with obesity volunteered and were randomly allocated into 1-year community-based behavioral weight-loss treatments with either a high ( n = 37) or moderate ( n = 41) focus on building self-regulatory skills to overcome lifestyle barriers. They were periodically assessed on measures of exercise- and eating-related self-regulatory skill usage, exercise- and eating-related barriers self-efficacy, exercise outputs, fruit/vegetable intake, and body composition. Reductions in weight and waist circumference, increases in exercise- and eating-related self-regulation and barriers self-efficacy, and increases in exercise and fruit/vegetable intake were each significant overall, and significantly greater in the group with a high self-regulatory skills-building focus. Change in barriers self-efficacy significantly mediated relationships between self-regulation change and changes in exercise outputs and fruit/vegetable intake from both baseline–Month 6 and baseline–Month 12. Change in barriers self-efficacy also significantly mediated relationships between change in self-regulation for eating from baseline–Month 3 and long-term changes in self-regulation for eating. Findings supported tenets of social cognitive, self-efficacy, and self-regulation theories: and indicated the importance of emphasizing, and facilitating a high amount of instruction and rehearsal time for self-regulatory skills development within behavioral weight-loss treatments. The ability to nurture self-efficacy through overcoming lifestyle barriers was also indicated.