OBJECTIVE: This systematic review aimed to evaluate the effects of hyaluronic acid (HA) alone or in combination with any bone substitute for the treatment of intrabony defects (IBDs). MATERIAL AND METHODS: Six databases were searched up to April 2022 to find randomized clinical trials comparing the clinical effects of open flap debridement (OFD) + HA versus OFD alone (first group) or OFD + HA + bone substitutes versus OFD + bone substitutes (second group) in the treatment of IBDs with a follow-up of at least 3 months. Random effects models of mean differences were used to determine the clinical attachment level (CAL) gain, probing depth (PD) reduction, and radiographic bone fill (RBF). RESULTS: Of the 276 studies identified, 6 were included in the qualitative synthesis, and 5 in the meta-analyses. The meta-analyses in the first group showed a statistically significant differences for CAL gain (mean difference [MD]:1.00; 95% confidence interval [CI]:0.65 - 1.35; n = 2) and PD reduction (MD: 0.76; 95%CI: 0.34 - 1.17; n = 2) favoring HA + OFD at 6 months. However, in the second group, the meta-analyses did no show additional effect of HA in association with bone substitute was demonstrated for either CAL gain (MD: 0.57; 95%CI: - 0.30 - 1.43; n = 2) or PD reduction (MD: 1.05; 95%CI: - 0.38 - 2.47; n = 2) but did show significant differences for RBF (MD: 0.57; 95%CI: 0.15 - 0.99; n = 2) at 12 months. CONCLUSION: Compared with OFD alone, local application of HA in the treatment of IBDs provided a significant CAL gain and PD reduction at 6 months. However, its combination with bone substitutes showed no statistically significant differences at 12 months. CLINICAL RELEVANCE: The use of OFD + HA improves the CAL and PD in the treatment of IBDs compared to OFD only after 6 months of follow-up. These results are not maintained after 12 months.