Purpose: The purpose of this study was to examine the association between adolescent and parental perceptions of neighborhood safety and adolescents' physical activity in multiple locations and to investigate the moderating effect of sex within this association. Method: This cross-sectional study was conducted with 928 adolescents aged 12 to 16 years old and 1 of their parents. Adolescents and parents reported their perceptions of neighborhood safety (traffic safety, pedestrian safety, crime safety, and stranger danger safety). Adolescents reported how often they were physically active in multiple locations (physical activity in the neighborhood, in parks, and for active transport). Mixed-effects linear regression models were used to investigate these associations while controlling for demographics and the Walkability Index. Results: Parent-perceived crime safety was positively associated with adolescents' physical activity in parks (B = 0.094, p = 0.024). Parent-perceived traffic safety was positively associated with adolescents' reported physical activity in the neighborhood (B = 0.186, p = 0.014). Adolescents' physical activity for active transport was positively associated with parent-perceived traffic safety (B = 0.179, p = 0.001), stranger danger safety (B = 0.110, p = 0.013), and crime safety (B = 0.077, p = 0.035). There were 2 interactions by sex on the relation between adolescent traffic safety perception and parent pedestrian safety perception in the neighborhood and adolescents' physical activity in parks (i.e., statistically significant only for boys). Conclusions: Parents' perceptions of traffic, stranger danger, and crime safety were all related to adolescents' active transportation. Multiple safety concerns may be motivating parents to restrict adolescent mobility by walking and bicycling.