Cranioplasty or cranial reconstruction is always a challenging procedure even for experienced surgeons. In this study, two different design techniques for customized cranial prostheses are assessed for cranial reconstruction. Mirror reconstruction is one of the commonly used reconstruction techniques that fails when cranial defects cross the midline of symmetry. Hence, there is a need for a design technique for the reconstruction of cranial defects irrespective of their location on the symmetrical plane. The anatomical reconstruction technique demonstrates its applicability for a wide spectrum of complex skull defects irrespective of the defective position in the anatomical structure. The paper outlines a methodological procedure involving a multi-disciplinary approach involving physicians and engineers in the design and reconstruction of customized cranial implants for asymmetrical skull defects. The proposed methodology is based on five foundation pillars including the multi-disciplinary approach, implant design process, additive-manufactured implant, implant fitting analysis, and cost and time analysis for the customized implant. The patient’s computed tomography scan data are utilized to model a customized cranial implant, which is then fabricated using electron beam melting technology. The dimensional validation of the designed and fabricated titanium implant based on the anatomical approach results in a precision of 0.6345 mm, thus indicating a better fit than the standard mirroring method. The results of fitting accuracy also reveal that the manufactured implant’s average deviation is very close to the planned reconstruction area with an error less than 1 mm, suggesting that the customized titanium implant fits the skull model quite precisely. The cost and time analysis reports that the cost for producing a customized cranial implant using electron beam melting technology is around USD 217.5 and the time taken to build is approximately 14 h and 27 min, which is low when compared to other studies. The cost and time analysis also demonstrates that the proposed design would be less burdensome to patients when compared to standard practice. Therefore, the new anatomical design process can be used effectively and efficiently to treat a number of diverse cranial abnormalities with the enhanced cranial implant design.