Symptomatic primary glenohumeral (GH) joint osteoarthritis (OA) can be challenging to treat. Hyaluronic acid (HA) has emerged as a promising treatment for the nonsurgical management of GH-OA. In this systematic review with meta-analysis, we aimed to evaluate the current evidence regarding the efficacy of intra-articular HA on pain relief in patients suffering from GH-OA. A total of 15 studies (only randomized controlled trials providing data at the end of the intervention) were included. The relevant studies were selected based on the following PICO model:​ P:​ patients with diagnosis of shoulder OA;​ I:​ HA infiltrations as therapeutic intervention administered;​ C:​ no restriction for comparators assessed;​ O:​ pain, in terms of visual analog scale (VAS) or numeric rating scale. The risk of bias among the included studies was estimated using the PEDro scale. A total of 1023 subjects were analyzed. Comparing HA injections combined with physical therapy (PT) compared to PT alone resulted in superior scores, showing an overall effect size (ES) of 4.43 (p = 0.00006). Moreover, pooled analysis of VAS pain scores demonstrated a significant improvement in the ES of the HA in comparison with corticosteroid injections (p = 0.002). On average, we reported a PEDro score of 7.2. A total of 46.7% of studies showed probable signs of a randomization bias. The findings of this systematic review and meta-analysis showed that IA injections of HA might be effective on pain relief with significant improvements compared to baseline and compared to corticosteroid injections in patients affected by GH-OA.