ObjectiveTo systematically review the effectiveness of different pharmacologic agents administered via ultrasound-guided intra-articular injection for pain relief and functional improvement in early-to-mid stage knee osteoarthritis. MethodsThe PubMed, Web of Science, Cochrane Library, Embase, CNKI, VIP, WanFang Data, SinoMed, ClinicalTrials.gov, and the WHO international clinical trials registry platform were electronically searched to collect randomized controlled trials (RCTs) related to the objectives from inception to May 8, 2025. Two reviewers independently screened literature, extracted data and assessed the risk of bias of the included studies. The network meta-analysis was then performed by using R 4.4.3 software. ResultsA total of 23 RCTs involving 1 587 participants and nine intervention strategies were included. The results revealed: (1) For pain relief, platelet-rich plasma combined with ultrasound guidance ranked highest; (2) In terms of functional improvement, platelet-rich plasma demonstrated consistent advantages across multiple dimensions of joint function, stiffness, and total score; (3) Hypertonic dextrose and autologous adipose tissue injections showed potential benefits in specific outcome dimensions; (4) Interventions such as traditional blind injections, corticosteroids, and ozone ranked moderately; (5) Safety: Based on limited reports, current evidence indicates that adverse events were predominantly mild and transient local reactions, with no serious events directly attributable to the interventions. ConclusionCurrent evidence shows that platelet-rich plasma under ultrasound guidance demonstrated a consistent advantage across multiple outcome measures, characterized by favorable safety, targeting precision, and clinical applicability.