We present a detailed step-by-step approach for the low-cost production and surgical implantation of cranial prostheses, aimed at restoring aesthetics, cerebral protection, and facilitating neurological rehabilitation. This protocol uses combined scan computed tomography (CT) cross-sectional images, in DICOM format, along with a 3D printing (additive manufacturing) setup. The in-house developed software InVesalius®️ is an open-source tool for medical imaging manipulation. The protocol describes image acquisition (CT scanning) procedures, and image post-processing procedures such as image segmentation, surface/volume rendering, mesh generation of a 3D digital model of the cranial defect and the desired prostheses, and their preparation for use in 3D printers. Furthermore, the protocol describes a detailed powder bed fusion additive manufacturing process, known as Selective Laser Sintering (SLS), using Polyamide (PA12) as feedstock to produce a 3-piece customized printed set per patient. Each set consists of a “cranial defect printout” and a “testing prosthesis” to assemble parts for precision testing, and a cranial “prostheses mold” in 2 parts to allow for the intraoperative modeling of the final implant cast using the medical grade Poly(methyl methacrylate) (PMMA) in a time span of a few min. The entire 3D processing time, including modelling, design, production, post-processing and qualification, takes approximately 42 h. Modeling the PMMA flap with a critical thickness of 4 mm by means of Finite Element Method (FEM) assures mechanical and impact properties to be slightly weaker than the bone tissue around it, a safety design to prevent fracturing the skull after a possible subsequent episode of head injury. On a parallel track, the Protocol seeks to provide guidance in the context of equipment, manufacturing cost and troubleshooting. Customized 3D PMMA prostheses offers a reduced operating time, good biocompatibility, and great functional and aesthetic outcomes. Additionally, it offers greater than 15-fold cost advantage over the usage of other materials, including metallic parts produced by additive manufacturing.