The purpose of this systematic review and meta-analysis was to compare functional outcomes and adverse events in the treatment of knee osteoarthritis with platelet-rich plasma (PRP) versus hyaluronic acid (HA) or placebo. The current meta-analysis included a total of nine randomized controlled trials, seven comparing PRP versus HA and two comparing PRP versus placebo, and calculated pooled estimates for the WOMAC total and sub-scores (pain, stiffness, function), Lequesne index, IKDC subjective score, EQ-VAS score, and risk of adverse events. PRP resulted in statistically significant improvements in the WOMAC total, IKDC and EQ-VAS scores when compared to hyaluronic acid (HA). The WOMAC total score was also more favourable in the PRP group when it was compared to placebo, but this difference was not statistically significant. There was no difference in the risk of adverse events when PRP was compared to HA or placebo.