The aim of this study was to evaluate the efficacy and safety of a single trigger point injection (TPI) of a local anesthetic for the treatment of myofascial pain syndrome (MPS) in patients with incurable cancer. This multicenter, exploratory, open-label, randomized comparative trial was conducted in five specialized palliative care departments. Hospitalized patients with incurable cancer who had been experiencing pain related to MPS were randomized to receive either a TPI of 1% lidocaine plus conventional care (TPI group) or conventional care alone (control group). The short-term efficacy and occurrence of adverse events were compared between groups. The primary endpoint was the percentage of patients who experienced a reduction in pain scores of ≥ 50%, assessed using an 11-point Numerical Rating Scale, at 3 days post-intervention. Adverse events were assessed using the Common Terminology Criteria for Adverse Events v5.0. Fifty patients were enrolled, and the trial completion rate was 100%. The proportion of patients who experienced an improvement in Numerical Rating Scale pain scores of ≥ 50% was 70.8% (95% confidence interval, 52.4% to 89.2%) in the TPI group and 0.0% in the control group; the difference was statistically significant (p < 0.001). In the TPI group, one case (4.2%) of Grade 1 nausea and one case (4.2%) of Grade 1 somnolence were reported. A single TPI of a local anesthetic is safe and efficacious in inducing an immediate reduction in MPS-related pain in patients with incurable cancer.