This systematic review and meta-analysis examines the relationship between running biomechanics and running economy (RE) in observational studies. The primary aim is to determine the associations between running biomechanics and RE and to explore potential causes of inconsistent findings. The review included 51 studies with 1115 participants, focusing on spatiotemporal, kinematic, kinetic, and electromyographic outcomes. Key findings include: 1. **Spatiotemporal Outcomes**: Most spatiotemporal outcomes showed trivial and non-significant associations with RE, except for a higher stride frequency, which was weakly but significantly associated with lower oxygen/energy cost (r = −0.20). 2. **Vertical Oscillation**: Higher vertical displacement of the pelvis/trunk/center of mass was moderately associated with higher oxygen/energy cost (r = −0.35). 3. **Kinematic Outcomes**: Ankle, knee, and hip angles at different phases in the gait cycle and their range of motion were not significantly associated with RE. 4. **Kinetic Outcomes**: Higher vertical and leg stiffness were moderately and significantly associated with lower oxygen/energy cost (r = −0.31 and −0.28, respectively). 5. **Mechanical Work Outcomes**: Total, negative, or positive mechanical work were not significantly associated with RE. 6. **Electromyographic Outcomes**: Surface electromyographic activation of various muscles during stance was not significantly associated with RE. 7. **Between-Group Comparisons**: The only significant between-group comparison was footstrike angle, showing no significant difference in RE between rearfoot and midfoot/forefoot strikers. The review also explored the impact of running speed, shoe standardization, RE units, and normalization of RE on the association between running biomechanics and RE. The findings suggest that biomechanical variables can explain 4–12% of the between-individual variance in RE when considered in isolation, with this magnitude potentially increasing when combining different variables. The implications for athletes, coaches, wearable technology, and researchers are discussed, highlighting the importance of understanding and modifying running biomechanics to improve RE.This systematic review and meta-analysis examines the relationship between running biomechanics and running economy (RE) in observational studies. The primary aim is to determine the associations between running biomechanics and RE and to explore potential causes of inconsistent findings. The review included 51 studies with 1115 participants, focusing on spatiotemporal, kinematic, kinetic, and electromyographic outcomes. Key findings include: 1. **Spatiotemporal Outcomes**: Most spatiotemporal outcomes showed trivial and non-significant associations with RE, except for a higher stride frequency, which was weakly but significantly associated with lower oxygen/energy cost (r = −0.20). 2. **Vertical Oscillation**: Higher vertical displacement of the pelvis/trunk/center of mass was moderately associated with higher oxygen/energy cost (r = −0.35). 3. **Kinematic Outcomes**: Ankle, knee, and hip angles at different phases in the gait cycle and their range of motion were not significantly associated with RE. 4. **Kinetic Outcomes**: Higher vertical and leg stiffness were moderately and significantly associated with lower oxygen/energy cost (r = −0.31 and −0.28, respectively). 5. **Mechanical Work Outcomes**: Total, negative, or positive mechanical work were not significantly associated with RE. 6. **Electromyographic Outcomes**: Surface electromyographic activation of various muscles during stance was not significantly associated with RE. 7. **Between-Group Comparisons**: The only significant between-group comparison was footstrike angle, showing no significant difference in RE between rearfoot and midfoot/forefoot strikers. The review also explored the impact of running speed, shoe standardization, RE units, and normalization of RE on the association between running biomechanics and RE. The findings suggest that biomechanical variables can explain 4–12% of the between-individual variance in RE when considered in isolation, with this magnitude potentially increasing when combining different variables. The implications for athletes, coaches, wearable technology, and researchers are discussed, highlighting the importance of understanding and modifying running biomechanics to improve RE.