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Simple Summary: Identifying the mutational landscape of tumors using next-generation sequencing (NGS) has become substantially more common over the past decade, especially in patients with advanced tumors. However, there is still limited real-world evidence for the clinical benefits of NGS-guided precision oncology. This retrospective analysis of breast and gynecological cancer patients referred to our center's multidisciplinary Molecular Tumor Board revealed that treatment recommendations were provided to 63.3% of patients, of whom 29.1% received molecular-matched treatment resulting in significantly prolonged progression-free survival. Commonly altered genes included TP53, PIK3CA, BRCA1/2, and ARID1A. Overall, NGS-guided precision oncology using panel diagnostics demonstrated improved clinical outcomes in a subset of patients with breast and gynecological cancers in a real-world setting. Background: Precision oncology treatments are being applied more commonly in breast and gynecological oncology through the implementation of Molecular Tumor Boards (MTBs), but real-world clinical outcome data remain limited. Methods: A retrospective analysis was conducted in patients with breast cancer (BC) and gynecological malignancies referred to our center's MTB from 2018 to 2023. The analysis covered patient characteristics, next-generation sequencing (NGS) results, MTB recommendations, therapy received, and clinical outcomes. Results: Sixty-three patients (77.8%) had metastatic disease, and forty-four patients (54.3%) had previously undergone three or more lines of systemic treatment. Personalized treatment recommendations were provided to 50 patients (63.3%), while 29 (36.7%) had no actionable target. Ultimately, 23 patients (29.1%) underwent molecular-matched treatment (MMT). Commonly altered genes in patients with pan-gyn tumors (BC and gynecological malignancies) included TP53 (n = 42/81, 51.9%), PIK3CA (n = 18/81, 22.2%), BRCA1/2 (n = 10/81, 12.3%), and ARID1A (n = 9/81, 11.1%). Patients treated with MMT showed significantly prolonged progression-free survival (median PFS 5.5 vs. 3.5 months, p = 0.0014). Of all patients who underwent molecular profiling, 13.6% experienced a major clinical benefit (PFSr ≥ 1.3 and PR/SD ≥ 6 months) through precision oncology. Conclusions: NGS-guided precision oncology demonstrated improved clinical outcomes in a subgroup of patients with gynecological and breast cancers. [ABSTRACT FROM AUTHOR]