We describe the use of ultrasound image guidance to improve treatment outcomes when administering interstitial photothermal therapy (I-PTT), an experimental cancer treatment modality. I-PTT is a promising thermal therapy for tumors using intratumorally injected nanoparticle-based photothermal agents activated by an interstitially placed laser diffuser. We hypothesized that ultrasound-based image guidance yields improved tumor treatment outcomes in terms of tumor regression and survival by improving the accuracy of the placement of the laser fiber and nanoparticles within a tumor and facilitating more precise PTT delivery. To test this hypothesis, we assessed the effect of ultrasound-guided I-PTT (US I-PTT) on neuroblastoma, an aggressive solid tumor of childhood, using the 9464D syngeneic model in C57BL/6 mice. US I-PTT using Prussian blue nanoparticles activated by an interstitial cylindrical laser diffuser generated an equivalent in vivo thermal dose as blinded, non-image-guided I-PTT (B I-PTT). However, US I-PTT resulted in significantly higher treatment accuracy compared to B I-PTT, attributable to the image guidance. Importantly, this improved accuracy translated to improved treatment outcomes wherein mice treated with US I-PTT exhibited significantly improved tumor regression, tumor-free survival, and long-term survival compared to mice treated with B I-PTT. Further, histological analyses of the tumors post-PTT confirmed the advantages conferred by US I-PTT over B I-PTT for tumor control. These proof-of-concept results demonstrate the value of using ultrasound guidance for I-PTT treatment and the translational implications of this approach to provide a more accurate and effective treatment for neuroblastoma.