Myofascial pain syndrome (MPS) is a prevalent condition that accounts for a significant proportion of musculoskeletal pain cases. Interfascial hydrodissection (IH) represents an innovative therapeutic intervention for MPS, particularly for those patients who have not found relief through conventional treatment methods. We conducted this study to evaluate the efficacy of the ultrasound-guided IH technique with 10% dextrose solution (D10W) for treating MPS. A retrospective analysis of clinical data was conducted from MPS patients who did not respond to conventional treatments. These patients subsequently received ultrasound-guided injections of D10W. The efficacy of this treatment modality was meticulously evaluated by quantitatively measuring the reduction in pain intensity in patients across 3 distinct posttreatment conditions: at rest, at nocturnal, and during exercise. Numerical Rating Scale and EQ-5D-5L were assessed at baseline, and at 4 and 12 weeks following the final injection. The pain scores, assessed 4 and 12 weeks posttreatment, demonstrated a significant reduction compared to pretreatment levels across rest, nocturnal, and exercise states (P < .05). The EQ-5D-5L results indicated that there were no significant differences in the dimensions of mobility, self-care, and usual activities when comparing before and posttreatment (P > .05). Conversely, a significant improvement was observed in the dimensions of pain/discomfort and anxiety/depression posttreatment relative to baseline measures (P < .05). No serious adverse effects were observed. Ultrasound-guided D10W IH has demonstrated significant efficacy in improving pain and alleviating anxiety/depression in patients with refractory MPS. The outcomes are promising for individuals with MPS who have not experienced improvement with conventional medical interventions.