Research examining gait biomechanics of persons with autism spectrum disorder (ASD) has grown significantly in recent years and has demonstrated that persons with ASD walk at slower self-selected speeds and with shorter strides, wider step widths, and reduced lower extremity range of motion and moments compared to neurotypical controls. In contrast to walking, running has yet to be examined in persons with ASD. The purpose of this study was to examine lower extremity running biomechanics in adolescents (13–18-year-olds) with ASD and matched (age, sex, and body mass index (BMI)) neurotypical controls. Three-dimensional kinematics and ground reaction forces (GRFs) were recorded while participants ran at two matched speeds: self-selected speed of adolescents with ASD and at 3.0 m/s. Sagittal and frontal plane lower extremity biomechanics and vertical GRF waveforms were compared using two-way analyses of variances (ANOVAs) via statistical parametric mapping (SPM). Adolescents with ASD ran with reduced stride length at self-selected speed (0.29 m) and reduced vertical displacement (2.1 cm), loading-propulsion GRFs (by 14.5%), propulsion plantarflexion moments (18.5%), loading-propulsion hip abduction moments (44.4%), and loading knee abduction moments (69.4%) at both speeds. Running at 3.0 m/s increased sagittal plane hip and knee moments surrounding initial contact (both 10.4%) and frontal plane knee angles during midstance (2.9 deg) and propulsion (2.8 deg) compared to self-selected speeds. Reduced contributions from primarily the ankle plantarflexion but also knee abduction and hip abduction moments likely reduced the vertical GRF and displacement. As differences favored reduced loading, youth with ASD can safely be encouraged to engage in running as a physical activity.