Introduction <p>The present meta-analysis compared intra-articular injections of hyaluronic acid (HA) versus plasma rich in growth factors (PRGF) in patients with knee osteoarthritis (OA). The outcome of interest was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).</p> Methods <p>This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses: the 2020 PRISMA statement. All the head-to-head randomised controlled trials (RCT) comparing intra-articular HA injections versus PRGF were accessed and included in the present study. Only studies that clearly stated that injections were performed in patients with knee OA, irrespective of the severity of OA, were considered. Data concerning the WOMAC index were retrieved at baseline and last follow-up. The endpoint of interest was to investigate whether intra-articular HA injections are associated with WOMAC score improvement compared to PRGF injections at 4–6 months follow-up.</p> Results <p>Data from 432 patients were collected and 76.3% (330 of 432) of the patients were women. The mean age of the patients was 58.2 ± 1.5&#xa0;years and the mean body mass index (BMI) was 28.0 ± 0.5 kg/m². At baseline, comparability in mean age, BMI, male:female ratio, WOMAC and related subscales were documented. The PRGF group evidenced lower values of the function subscale of the WOMAC index (<i>P</i> = 0.03). No difference was found in the overall WOMAC index (<i>P</i> = 0.05) and its stiffness (<i>P</i> = 0.4) and pain (<i>P</i> = 0.07) subscales.</p> Conclusion <p>The current level&#xa0;I evidence suggests that the use of PRGF might be associated with more favorable clinical outcomes than using HA.</p>