Surgical site infections (SSIs) remain a significant concern in abdominal surgeries, contributing to prolonged hospitalization, increased healthcare costs, and morbidity. The aim of this case-control study was to investigate the role of comorbidities in predicting the occurrence of SSIs in abdominal surgery patients. A cohort of 200 patients undergoing elective abdominal surgery at a tertiary care hospital was analyzed, with 100 patients developing SSIs and 100 matched controls. The study evaluated the impact of various comorbid conditions, including diabetes mellitus, hypertension, and obesity, on the incidence of SSIs. Statistical analysis revealed a significant association between diabetes (p < 0.001), obesity (p < 0.01), and hypertension (p < 0.05) with higher rates of infection. The odds ratios for diabetes and obesity were 3.5 (95% CI: 2.0–5.0) and 2.1 (95% CI: 1.5–3.2), respectively. This study emphasizes the importance of preoperative assessment of comorbid conditions in predicting SSIs. Additionally, the findings suggest that targeted interventions to optimize comorbidity management may reduce the risk of SSIs. These results contribute to a deeper understanding of SSI pathogenesis and underscore the need for personalized surgical care strategies.