Objective <p>To develop a prognostic model that predicts outcomes and identifies ideal candidates for metastasis-directed therapy (MDT) in patients with de novo metastatic nasopharyngeal carcinoma (dmNPC) after chemo-immunotherapy and locoregional radiotherapy (LRRT).</p> Methods <p>Dm NPC patients receiving chemo-immunotherapy followed by LRRT across four centers were enrolled. Propensity score matching (PSM) analysis was conducted to compare progression-free survival (PFS) between patients who received MDT and those who did not. A predictive nomogram was developed to stratify patients and identify candidates for MDT.</p> Results <p>A total of 364 patients were included in this study. Of these, 94 patients received MDT, while 270 patients did not. PSM analysis revealed that MDT was associated with a significant PFS benefit (HR: 0.6; 95% CI, 0.38–0.93; <i>p</i> = 0.024). A prognostic nomogram was conducted based on three independent prognostic factors: posttreatment EBV DNA, age, and the number of metastatic lesions. In the low-risk group identified by the nomogram, patients receiving MDT exhibited significantly improved PFS compared to those who did not (median PFS, not reached vs. 37.8 months, <i>p</i> = 0.014). However, no significant difference was observed in the high-risk group (median PFS, 18.8 months vs. 13.7 months, <i>p</i> = 0.74).</p> Conclusion <p>MDT was associated with improved PFS in dm NPC patients, especially in those classified as low-risk.</p>