Background: Inferior alveolar nerve block (IANB) is essential for many surgical and endodontic procedures. It requires accurate needle placement due to its high failure rate. Purpose: The article was undertaken to assess the location of the targeted mandibular foramen and to present a proof of concept (PoC) of a novel customized modified surgical guide for blocking the inferior alveolar nerve. Materials and Methods: The location of this foramen was determined in 360 mandibular rami in 180 cone-beam computed tomography scans of the mandible from the premolar region of the opposite side. A novel customized 3D-printed implant surgical guide was modified after determining the suitable IANB needle direction on 3D images generated from digital dental model images and cone-beam computed tomography (CBCT) scans for 8 lower posterior implant cases. Results: The distance from the IANB targeted foramen to the premolar region of the opposite side could be measured in all CBCT scans and showed many variations. The CBCT-based analysis of the mandibular foramen location could be fused with digital dental images for the modification of the new device for IANB. The concept of determining the path of needle insertion for the design and fabrication of a modified 3D-printed surgical guide for IANB was found to be feasible. Conclusions: The location of the mandibular foramen could be determined in CBCT scans with its variations. A proof of concept (PoC) of a new customized device for IANB computer guided accurate needle penetration could be presented. The new modified 3D-printed guide may offer the advantages of more accurate IANB injection with an exact three-dimensional determination of the path of needle insertion.