The purpose of this study was to investigate the effects of structured physical activity program on social interaction and communication of children with autism spectrum disorder (ASD). Fifty children with ASD from a special school were randomly divided into experimental and control groups. 25 children with ASD were placed in the experimental group, and the other 25 children as the control group participated in regular physical activity. A total of forty-one participants completed the study. A 12-week structured physical activity program was implemented with a total of 24 exercise sessions targeting social interaction and communication of children with ASD, and a quasi-experimental design was used for this study. Data were collected using quantitative and qualitative instruments. SSIS and ABLLS-R results showed that an overall improvement in social skills and social interaction for the experimental group across interim and posttests, F = 8.425, p = 0.001 (p < 0.005), and significant improvements appeared in communication, cooperation, social interaction, and self-control subdomains (p < 0.005). Conversely, no statistically significant differences were found in the control group (p > 0.005). The study concluded that the special structured physical activity program positively influenced social interaction and communication skills of children with ASD, especially in social skills, communication, prompt response, and frequency of expression.