Despite the evident benefits of the modern surgery-first orthognathic surgery approach (reduced treatment time, efficient tooth decompensation, and early improvement in facial esthetics), the challenge of the surgical-occlusion setup acts as a hindering factor for the widespread and global adoption of this therapeutic modality, especially for the management of cleft-skeletofacial deformity. This is the first study to assess three-dimensional (3D) quantitative data of the surgical-occlusion setup in surgery-first cleft-orthognathic surgery. This comparative retrospective study was performed on 3D image datasets from consecutive patients with skeletal Class III deformity who had a unilateral cleft lip/palate (cleft cohort, n = 44) or a noncleft dentofacial deformity (noncleft cohort, n = 22) and underwent 3D computer-assisted single-splint two-jaw surgery by a single multidisciplinary team between 2014 and 2018. They received conventional orthodontics-first or surgery-first approaches. 3D quantitative characterization (linear, angular, and positional measurements) of the final surgical-occlusion setup was performed and adopted for comparative analyses. In the cleft cohort, the occlusion setup in the surgery-first approach had a significantly (all p < 0.05) smaller number of anterior teeth contacts and larger incisor overjet compared to the conventional approach. Considering the surgery-first approach, the cleft cohort presented significantly (all p < 0.05) larger (canine lateral overjet parameter) and smaller (incisor overjet, maxillary intercanine distance, maxillary intermolar distance, ratio of intercanine distance, and ratio of intermolar distance parameters) values than the noncleft cohort. This study contributes to the literature by providing 3D quantitative data of the surgical-occlusion setup in surgery-first cleft-orthognathic surgery, and delivers information that may assist multidisciplinary teams to adopt the surgery-first concept to optimize cleft care.