The incidence of differentiated thyroid cancer has increased significantly during the last several decades. Surgical resection is the primary treatment for thyroid cancer and is highly effective, resulting in 5-year survival rates greater than 98%. However, surgical resection can result in short- and long-term treatment-related morbidities. Additionally, as this malignancy often affects women less than 40 years of age, there is interest in more conservative treatment approaches and, an unmet need for therapeutic options that minimize the risk of surgery-related morbidities while simultaneously providing an effective cancer treatment. Photodynamic therapy (PDT) has the potential to reduce treatment-related side effects by decreasing invasiveness and limiting toxicity. Owing to multiple advantageous properties of the porphyrin-HDL nanoparticle (PLP) as a PDT agent, including preferential accumulation in tumor, biodegradability and unprecedented photosensitizer packing, we evaluate PLP-mediated PDT as a minimally invasive, tumor-specific treatment for thyroid cancer. On both a biologically relevant human papillary thyroid cancer (K1) mouse model and an anatomically relevant rabbit squamous carcinoma (VX2)-implanted rabbit thyroid model, the intrinsic fluorescence of PLP enabled tracking of tumor preferential accumulation and guided PDT. This resulted in significant and specific apoptosis in tumor tissue, but not surrounding normal tissues including trachea and recurrent laryngeal nerve (RLN). A long-term survival study further demonstrated that PLP-PDT enabled complete ablation of tumor tissue while sparing both the normal thyroid tissue and RLN from damage, thus providing a safe, minimally invasive, and effective alternative to thyroidectomy for thyroid cancer therapies.