<p>Anatomical variations in the sphenoid sinus (SS) and adjacent neurovascular structures differ between sexes, impacting surgical approaches such as endoscopic sinus surgery and transsphenoidal procedures. This study evaluates sex-based morphometric and structural differences in the SS using computed tomography (CT). A prospective CT-based analysis was performed to assess sphenoid sinus volume, pneumatization patterns, and the anatomical relationship of surrounding neurovascular structures in male and female patients. Linear distances and frequency of structural protrusions and dehiscence were compared between sexes using statistical analysis. This study comprehensively evaluated anatomical variations of the sphenoid sinus in a cohort of 200 individuals aged 14 to 87 years, with the aim of identifying clinically significant differences across age groups and between genders that are crucial for surgical planning, particularly in transsphenoidal and endoscopic skull base procedures. The mean age was 46.05 ± 15.75 years, with a male predominance (60%), yielding a male-to-female ratio of 1.5:1. The sellar type of sphenoid pneumatization was the most prevalent (77%), followed by presellar (18.5%) and conchal (3.5%) types. Onodi cells were absent in 77.5% of cases and most commonly present bilaterally when seen. Lateral recess pneumatization was observed in 28% of subjects, while a single intersinus septum was the most frequent septation pattern (59.5%). Septal attachments to critical neurovascular structures were uncommon but clinically important, with attachment to the left carotid canal (13%) being more frequent than to the right carotid or optic canals. According to the De Lano classification, Type 1 pneumatization was the most common bilaterally. Age-related analysis showed no statistically significant variation in De Lano types, though a trend toward increased carotid canal protrusion with age was noted. Gender-based differences were significant for carotid canal protrusion and left vidian canal dehiscence, both more prevalent in males (<i>p</i> &lt; 0.05). Overall, right vidian canal dehiscence (26.5%) was the most common bony dehiscence, followed by left vidian (20.5%) and carotid canal protrusion (right: 19.5%, left: 23.6%). Foramen rotundum dehiscence was rare, especially on the left (3.5%). Linear morphometric measurements demonstrated general symmetry across the midline, with no significant age-based variation. Notably, right vidian canal dehiscence showed a significant increase with age (<i>p</i> = 0.002), while sinus volume and neurovascular distances remained relatively stable. These results emphasize the importance of individualized imaging assessment, particularly in male and elderly patients, to identify anatomical variants that could increase the risk of surgical complications. It underscores the intricate anatomical variability of the sphenoid sinus and the necessity for individualized radiological assessments. Detailed preoperative imaging not only facilitates surgical planning but also reduces the risk of potentially devastating complications. Recognizing population-specific morphologies enhances both surgical safety and precision, making detailed anatomical mapping an indispensable component of modern sinus and skull base surgery.</p>