Brachytherapy can provide sufficient doses to head and neck squamous cell carcinoma (HNSCC) with minimal damage to nearby normal tissues. In this study, the β−-emitter177 Lu was conjugated to DTPA-polyethylene glycol (PEG) decorated gold nanostars (177 Lu-DTPA-pAuNS) used in surface-enhanced Raman scattering and photothermal therapy (PTT). The accumulation and therapeutic efficacy of177 Lu-DTPA-pAuNS were compared with those of177 Lu-DTPA on an orthotopic HNSCC tumor model. The SPECT/CT imaging and biodistribution studies showed that177 Lu-DTPA-pAuNS can be accumulated in the tumor up to 15 days, but177 Lu-DTPA could not be detected at 24 h after injection. The tumor viability and growth were suppressed by injected177 Lu-DTPA-pAuNS but not nonconjugated177 Lu-DTPA, as evaluated by bioluminescent imaging. The radiation-absorbed dose of the normal organ was the highest in the liver (0.33 mSv/MBq) estimated in a 73 kg adult, but that of tumorsphere (0.5 g) was 3.55 mGy/MBq, while intravenous injection of177 Lu-DTPA-pAuNS resulted in 1.97 mSv/MBq and 0.13 mGy/MBq for liver and tumorsphere, respectively. We also observed further enhancement of tumor-suppressive effects by a combination of177 Lu-DTPA-pAuNS and PTT compared to177 Lu-DTPA-pAuNS alone. In conclusion,177 Lu-DTPA-pAuNS may be considered as a potential radiopharmaceutical agent for HNSCC brachytherapy.