The transpedicular screw placement has been the gold standard for over a decade in treating degenerative diseases of the lumbo-sacral spine related to vertebral instability. The evolution of neuronavigation and robotic surgery has mitigated many perioperative complications such as mispositioning, vascular damage, and nerve structure injuries, leading to enhanced postoperative outcomes, reduced blood loss, and decreased intraoperative radiation exposure. Our study proposes a multicenter comparison between robotic surgery and neuronavigation for treating degenerative diseases of the lumbo-sacral spine. We conducted a retrospective analysis at Papardo Hospital in Messina and Garibaldi Hospital in Catania, examining a consecutive series of 76 patients treated for degenerative diseases of the lumbo-sacral spine between March 2024 and December 2024 using the Excelsius GPS Robot and neuronavigation with the O-arm. We evaluated each procedure based on age, sex, body mass index, number of involved metameres, number of screws placed, operative times, estimated blood loss (EBL), radiation exposure, type of anesthesia, accuracy (using the Gertzbein and Robbins scale), and then compared various pre- and postoperative parameters through univariate statistical analysis. Patients were randomly assigned in a 1:1 ratio using a computer-generated sequence with permuted blocks of variable size (4-6). This ensured balanced allocation and minimized selection bias. A detailed statistical plan has been included: continuous variables were assessed using Student's t-test or Mann-Whitney U test depending on distribution (Shapiro-Wilk test), while categorical variables were evaluated with Chi-square or Fisher's exact test as appropriate. 48 out of 76 patients (average age 60.47 years) underwent pedicle screw placement via robotic surgery, and 28 patients (average age 65.92 years) via neuronavigation surgery. Robotic surgery showed comparable results to neuronavigation surgery in terms of blood loss. Additionally, functional outcomes, especially those evaluated with the ODI scale and VAS scale, were similar between the two patient groups. Despite a reported mispositioning rate of 2.2% in neuronavigation surgery, no clinical impact was observed in these specific cases. The surgical procedures included both decompression (laminectomy with partial facetectomy) and fusion in all patients. Operative time was recorded as skin-to-skin time, excluding anesthesia induction and positioning. Patients with prior surgeries at the index level, complex spinal deformities (Cobb angle > 30°), or revision surgeries were excluded from this study. The included diagnoses were degenerative disc disease (RS: 56%, NS: 52%), spinal stenosis (RS: 28%, NS: 31%), spondylolisthesis (RS: 12%, NS: 14%), and traumatic pathology (RS: 4%, NS: 3%). While there was a trend towards greater precision in screw placement with robotic technology, no significant difference was observed compared to neuronavigation with the O-arm. Both technological systems used in instrumented spinal surgery appear safe and effective. However, they present a steep learning curve, and various technical aspects of these systems are continuously reassessed to improve operational efficiency and achieve these objectives.