Background: In the context of precision diagnosis for various subtypes of melanoma, identifying biomarkers with clinical translational potential from a molecular standpoint is crucial for a more comprehensive characterization of the disease. MUC18 is highly expressed in both tumor cells and tumor vasculature in major melanoma subtypes and is restricted to normal tissues. Methods: A noninvasive imaging approach for MUC18 in melanoma utilizing an immune Positron Emission Tomography (PET) radionuclide-conjugated drug (RDC) with an 89Zr-labeled humanized anti-MUC18 monoclonal antibody (mAb) was developed. A375, Sk-Mel-28, HMVII, and A549 cells and tumor model mice were conducted. Immuno-PET was employed to assess the specificity and targeting of three distinct melanoma cell line-derived xenografts (CDXs) and patient-derived tumor xenografts (PDXs) in immunodeficient mice. Results: The developed RDC, named 89Zr-IP150, demonstrated robust in vitro stability and high binding affinity, ensuring reliable and specific PET imaging of small, medium, and large subcutaneous tumors in human melanoma mouse xenotransplantation models. Notably, for the first time, the clinical translational potential of 89Zr-IP150 was successfully validated using a PDX model. Conclusions: These findings present a noninvasive, real-time method for the early screening of MUC18 (+) melanoma patients and are important for studying the early-stage biological distribution of MUC18-targeted antibody‒drug conjugates (ADCs).