OBJECTIVES: There is a discrepancy between evidence in support of the widespread use of intra-articular hyaluronic acid (IAHA) to treat knee osteoarthritis (OA) in clinical practice, and the often discordant recommendations from multiple international guideline committees, which requires further investigation. METHODS: We conducted a literature review to determine the strength of evidence in support of the efficacy and safety of IAHA, from randomized controlled trials and meta-analyses. RESULTS: Our analysis shows that IAHA provides a moderate symptomatic benefit to knee OA patients and without major safety concerns. In fact, IAHA may offer one of the best benefit/risk ratios among pharmacologic options, as measured by improvements in knee OA health outcomes, overall gain in quality-adjusted life years and substantial delays in time to total knee replacement. CONCLUSIONS: We advocate for the consideration of recommending IAHA injection as a treatment option in the management of knee OA, tailored by disease stage and patient phenotype. Future research efforts should focus on identification of OA patient subgroups that demonstrate a more robust response to IAHA, determination of long-term effects of repeat IAHA injections on patient-reported outcomes and total knee replacement-sparing effect, further elucidation of disease-modifying effects, and the potential for combination therapy with other pharmacologic and non-pharmacologic therapies to optimize the management of knee OA.