This study explored the efficacy of a lay health worker (LHW)-led physical activity (PA) counselling program for inactive patients with HIV/AIDS and mental health problems living in a Ugandan farming community. In total 49 (35 women) community patients (40.0 ± 11.2 years) followed an 8-week once weekly LHW-led PA counselling program based on a self-determination theory and motivational interviewing framework. Participants completed the Simple Physical Activity Questionnaire, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, HIV/AIDS Stress Scale and World Health Organization Disability Assessment Schedule 2 (WHODAS 2) pre- and immediately post-intervention. Small, significant (< 0.05) effect sizes were found for reductions in HIV/AIDS-related stress (Cohen's d = 0.26) and in global disability (Cohen's d = 0.46). Large effect sizes were observed for reductions in time spent sedentary (Cohen's d = 1.97) and reductions in depressive (Cohen's d = 2.04) and anxiety (Cohen's d = 1.47) symptoms and increases in time spent active (Cohen's d = 1.98). Greater decrease in sedentary time was associated with greater anxiety symptoms reduction ( = 0.32,  = 0.021). In physically inactive patients with HIV/AIDS and mental health problems, an LHW-led PA counselling program reduced stress, anxiety, depression and disability. Randomized controlled trials are needed to confirm these preliminary positive findings.