Background <p>Knee Osteoarthritis (KOA) is a degenerative joint condition that leads to pain and limited mobility. Non-invasive treatments like Low-Intensity Pulsed Ultrasound (LIPUS) and Extracorporeal Shockwave Therapy (ESWT) help manage symptoms and support recovery. While both methods are effective, no studies have directly compared ESWT alone to its combination with LIPUS (LESWT) for KOA. This study aims to assess their efficacy and provide evidence for treatment choices.</p> Methods <p>This randomized controlled trial (RCT) used computer-generated block randomization with allocation concealment via sequentially numbered opaque envelopes. Outcome assessors were blinded to treatment allocation; though complete patient blinding was not feasible due to the physical nature of the interventions (LESWT vs. ESWT). Radial extracorporeal shock wave therapy (R-ESWT) was administered using a radial applicator (MASTERPULS MP100 Ultra; Storz Medical, Switzerland) at 10&#xa0;Hz and 3&#xa0;bar with 2,000 impulses per session. LIPUS was applied at 1&#xa0;MHz and 0.5 W/cm² for 20-min daily sessions. The study included 110 patients with KOA who underwent LESWT, forming the LESWT group, and another 110 KOA patients who were treated with R-ESWT, constituting the R-ESWT group. Evaluations were conducted to compare clinical outcomes, levels of inflammatory markers in joint synovial fluid, and the occurrence of adverse events before and after the treatment.</p> Results <p>The LESWT group showed a higher clinical effective rate (81.57%) compared to the R-ESWT group (64.82%, <i>p</i> &lt; 0.01), with greater improvements in the Lysholm Knee Scoring Scale (LKSS), Visual Analog Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and range of motion (ROM) scores (<i>p</i> &lt; 0.05). Levels of inflammatory markers (nitric oxide [NO], interleukin-1β [IL-1β], tumor necrosis factor-α [TNF-α], matrix metalloproteinase-3 [MMP-3]) declined, whereas superoxide dismutase [SOD] and transforming growth factor-β1 [TGF-β1] levels rose, with the LESWT group exhibiting more pronounced changes (<i>p</i> &lt; 0.01). The occurrence of adverse events showed no significant difference between the groups (<i>p</i> &gt; 0.05).</p> Conclusion <p>LESWT demonstrates significant efficacy in alleviating pain and reducing inflammatory markers in patients with KOA, making it a promising therapeutic option deserving of further clinical consideration.</p> Trial registration <p>The study protocol was registered on ClinicalTrials.gov registration with the register number CTR2457249805 (registration date: 2022/08/03).</p>