In recent years, various clinical trials have focused on treating knee osteoarthritis (KOA) with multiple injections of platelet-rich plasma (PRP). However, compared with the multiple hyaluronic acid (m-HA) injections, the clinical efficacy of multiple PRP (m-PRP) injections for KOA still remains controversial among these studies. Therefore, we aimed to compare the clinical effectiveness of m-PRP injections with m-HA injections in the treatment of KOA in this systematic review. Relevant clinical trials were searched via bibliographic databases, including Medline, PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials, to compare the m-PRP and m-HA injections in the treatment of KOA. Finally, fourteen randomized controlled trials, including 1512 patients, showed the postoperative VAS, WOMAC, IKDC, or EQ-VAS scores and were enrolled in this systematic review. Compared with the group of intra-articular m-HA injections, the group of intra-articular m-PRP injections was lower in the VAS scores at 3-month (WMD = -0.25; 95%CI, -0.40 to -0.10, p = 0.0009) and 12-month (WMD = -0.64; 95%CI, -0.79 to -0.49, p < 0.00001) follow-ups. In addition, the group of intra-articular m-PRP injections was also lower in the WOMAC scores at 1-month (WMD = -1.23; 95%CI, -2.17 to -0.29, p = 0.01), 3-month (WMD = -5.34; 95%CI, -10.41 to -0.27, p = 0.04), 6-month (WMD = -11.02; 95%CI, -18.09 to -3.95, p = 0.002), and 12-month (WMD = -7.69; 95%CI, -12.86 to -2.52, p = 0.004) follow-ups. Furthermore, compared with the group of intra-articular m-HA injections, the group of intra-articular m-PRP injections was higher in the IKDC scores at 3-month (WMD = 7.45; 95%CI, 2.50 to 12.40, p = 0.003) and 6-month (WMD = 5.06; 95%CI, 1.94 to 8.18, p = 0.001) follow-ups. However, the long-term adverse side of m-PRP injections for KOA still needs more large-scale trials and long-term follow-ups.