The utilization of compression garments (CGs) has demonstrated the potential to improve athletic performance; however, the specific mechanisms underlying this enhancement remain a subject of further investigation. This study aimed to examine the impact of CGs on running mechanics and muscle synergies from a neuromuscular control perspective. Twelve adult males ran on a treadmill at 12 km/h, while data pertaining to lower limb kinematics, kinetics, and electromyography were collected under two clothing conditions: whole leg compression garments and control. The Non-negative matrix factorization algorithm was employed to extract muscle synergy during running, subsequently followed by cluster analysis and correlation analysis. The findings revealed that the CGs increased knee extension and reduced hip flexion at foot strike compared with the control condition. Moreover, CGs were found to enhance stance-phase peak knee extension, while diminishing hip flexion and maximal hip extension during the stance-phase, and the ankle kinematics remained unaltered. We extracted and classified six synergies (SYN1-6) during running and found that only five SYNs were observed after wearing CGs. CGs altered the structure of the synergies and changed muscle activation weights and durations. The current study is the first to apply muscle synergy to discuss the effect of CGs on running biomechanics. Our findings provide neuromuscular evidence for the idea of previous studies that CGs alter the coordination of muscle groups, thereby affecting kinematic characteristics during running.