We describe an innovative approach to teaching homeless men the critical thinking skills underlying adaptive decision making and self-regulation needed to bolster resilience in the face of multiple and complex personal challenges. Single men living in a transitional housing facility for the homeless were taught the BrainWise curriculum (n = 210) along with other educational, career, and life skills programs, and tested 4 months later. This group was compared with a smaller control group (n = 61) of men from the same and similar facilities. Outcomes were measured through self-reports of executive functions (Behavior Rating Inventory of Executive Function [BRIEF]), problem solving (Wasik Problem Solving Rating Scale [WPSRS]), coping (Coping Self-Efficacy [CSE]), and knowledge of the thinking skills taught through BrainWise (BrainWise Knowledge Survey [BKS]). All measures showed adequate internal consistency reliability and less strong, but significant, test-retest stability. As expected, self-reported skills in executive function, coping self-efficacy, problem solving, and BrainWise knowledge covaried in predictable ways. The attrition between the pretest and posttest was not predicted by any of the major outcome measures. The sample of 108 men in the Treatment Group who were still in the program 4 months later exhibited significant improvements on all BRIEF composites and subscales, CSE, and the BKS, but not on the WPSRS. In contrast, the remaining 37 Control Group men showed many fewer improvements in the BRIEF scores and a decrease in the WPSRS score. The results suggest the efficacy of BrainWise and measurement of these skills in the vulnerable population of homeless individuals; however, challenges of this type of research and limitations of this study are discussed.