30 blinded randomized controlled trials evaluating the use of hyaluronic acid injections in comparison to a placebo injection in patients with knee osteoarthritis were included in this systematic review and meta-analysis. The objective of this systematic review and meta-analysis was to compare the efficacy and safety of hyaluronic acid injections across different dosing regimens. At 3 months, data were available for 2-4 injection and 5+ injection groups. The 2-4 injection groups demonstrated significantly lower pain scores compared placebo (SMD -0.76 p<0.00001), while the 5+ injection groups did not demonstrate significantly lower pain compared to placebo (SMD -0.20; p=0.09). At 6 months, both the 2-4 injection group (SMD -0.36; p=0.008) and 5+ injection group demonstrated significantly lower pain compared to placebo (SMD -0.18; p=0.04). The single injection groups did not significantly reduce pain compared to placebo at 6 months (SMD -0.04; p=0.67). When looking at the incidence of adverse events, only the 5+ injection group demonstrated a significantly greater incidence compared to placebo (RR 1.67; p=0.02).