Neuroblastoma (NB) is one of the most common pediatric malignancies. Approximately half of patients diagnosed with this disease are classified as “high-risk,” which is defined as metastasized or aggressive NB with a poor prognosis if not treated properly. Treatment of high-risk neuroblastoma (HRNB) often requires an integrated approach involving chemotherapy, surgery, immunotherapy, radiotherapy, cancer vaccines, and autologous stem cell transplantation. As HRNB is highly infiltrative, frequently wraps around blood vessels, and is often difficult to differentiate from normal tissues, a surgical procedure that employs tools which optimize real-time, intraoperative visualization of the tumor is essential. This is now achievable by a tracer that is cancer target-specific and a fluorescence-labeled monoclonal antibody (mAb) that can improve the quality of complete tumor removal. Fluorescence-guided surgery (FGS) has been proven to provide qualitative and quantitative imaging and real-time mapping of tumors using tumor-specific targets for HRNB. GD2, a disialoganglioside glycolipid, and a clinically significant tumor-associated antigen, has been shown to overexpress on the surface of NB cells and is minimally expressed in normal cells. The tumor-selective anti-GD2 monoclonal antibody (anti-GD2 mAb) has been used in immunotherapy in treating HRNB patients with success and has demonstrated clear benefit. Thus, fluorescence-tagged anti-GD2 mAb could function as a visual tracer that guides surgical procedures specific for HRNB to optimize tumor resection with greater accuracy, thereby lowering the risk of surgical complications and reducing the incidence of relapse. We provide a critical review of current treatment strategies and future applications of targeted FGS in HRNB treatment.