Uterine leiomyosarcoma (LMS) represents a rare yet highly aggressive tumor, comprising approximately 1% of uterine malignancies. First-line regimens involving doxorubicin or gemcitabine and docetaxel demonstrate modest response rates. Notably, the combination of doxorubicin plus trabectedin has emerged as a preferred first-line option following the LMS-04 study, showing superior progression-free survival compared to doxorubicin alone. Second-line therapy for recurrent LMS poses greater challenges, with single-agent treatments exhibiting limited efficacy. Herein, we present a case of a 65-year-old woman with stage 1B uterine leiomyosarcoma, previously treated with surgical resection and adjuvant gemcitabine/docetaxel, due to surgical morcellation. Despite initially achieving disease-free status, she experienced a first recurrence 5 years later, treated with surgery and radiation, and a second recurrence 4 years after, necessitating second-line therapy with doxorubicin and trabectedin. The patient exhibited a remarkable response to this regimen, achieving partial response after 6 cycles of doxorubicin and trabectedin chemotherapy. She maintained stable disease over 13 cycles of maintenance trabectedin and 6 months off treatment, for a total of 16 months of progression-free survival. This case underscores the potential efficacy of combination chemotherapy with doxorubicin and trabectedin as a second-line treatment option for recurrent uterine leiomyosarcoma.