Running biomechanics is considered an important determinant of running economy (RE). However, studies examining associations between running biomechanics and RE report inconsistent findings. The aim of this systematic review was to determine associations between running biomechanics and RE and explore potential causes of inconsistency. Three databases were searched and monitored up to April 2023. Observational studies were included if they (i) examined associations between running biomechanics and RE, or (ii) compared running biomechanics between groups differing in RE, or (iii) compared RE between groups differing in running biomechanics during level, constant-speed, and submaximal running in healthy humans (18-65 years). Risk of bias was assessed using a modified tool for observational studies and considered in the results interpretation using GRADE. Meta-analyses were performed when two or more studies reported on the same outcome. Meta-regressions were used to explore heterogeneity with speed, coefficient of variation of height, mass, and age as continuous outcomes, and standardization of running shoes, oxygen versus energetic cost, and correction for resting oxygen or energy cost as categorical outcomes. Fifty-one studies (n = 1115 participants) were included. Most spatiotemporal outcomes showed trivial and non-significant associations with RE: contact time r = - 0.02 (95% confidence interval [CI] - 0.15 to 0.12); flight time r = 0.11 (- 0.09 to 0.32); stride time r = 0.01 (- 0.8 to 0.50); duty factor r = - 0.06 (- 0.18 to 0.06); stride length r = 0.12 (- 0.15 to 0.38), and swing time r = 0.12 (- 0.13 to 0.36). A higher cadence showed a small significant association with a lower oxygen/energy cost (r = - 0.20 [- 0.35 to - 0.05]). A smaller vertical displacement and higher vertical and leg stiffness showed significant moderate associations with lower oxygen/energy cost (r = 0.35, - 0.31, - 0.28, respectively). Ankle, knee, and hip angles at initial contact, midstance or toe-off as well as their range of motion, peak vertical ground reaction force, mechanical work variables, and electromyographic activation were not significantly associated with RE, although potentially relevant trends were observed for some outcomes. Running biomechanics can explain 4-12% of the between-individual variation in RE when considered in isolation, with this magnitude potentially increasing when combining different variables. Implications for athletes, coaches, wearable technology, and researchers are discussed in the review.