Background Pseudoexfoliation syndrome (PEX) is characterized by a dandruff-like substance in the anterior chamber, composed of various glycoproteins that have an unclear origin. Its deposition is observed on the pupillary margin, lens zonules, and trabecular meshwork. Proteomic studies have identified numerous proteins in the affected individuals, suggesting associations with systemic conditions like heart disease, stroke, and Alzheimer's disease. However, the systemic associations of PEX remain inconclusive, particularly in regions like southern India. Materials and methods A cross-sectional study was conducted on 114 participants. Pseudoexfoliation was graded as mild, moderate, and severe as per standard photographic grading. Systemic examinations included blood pressure measurements, electrocardiography (ECG), and blood investigations for serum lipid profile, fasting and postprandial blood sugar levels, and serum C-reactive protein levels. Small incision cataract surgery was performed for all the patients. Intraoperative complications and postoperative status were recorded. Results Thirty-eight patients (33.3%) had mild PEX, 44 (38.6%) had moderate PEX, and 32 (28.1%) had severe PEX. Hypertension was present in 54 participants (47.4%), diabetes in 21 (18.4%), coronary artery disease in nine (7.9%), and cerebrovascular accidents in three (2.6%). The mean systolic blood pressure was 140.39 mmHg and the mean diastolic blood pressure was 90.37 mmHg. Systolic blood pressure exceeded 140 mmHg in 29 participants (90.6%) with severe PEX, while diastolic blood pressure surpassed 90 mmHg in 26 participants with severe PEX, both with a p-value of 0.001. Mean fasting and postprandial blood sugar levels were 103.80 ± 31.81 mg/dl and 131.72 ± 48.24 mg/dl, respectively. Serum lipid profiles showed mean low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), cholesterol, and triglyceride levels of 103.00 ± 34.49 mg/dl, 29.04 ± 15.51 mg/dl, 172.73 ± 43.34 mg/dl, and 129.33 ± 64.65 mg/dl respectively. Electrocardiographic results indicated that 54 participants (47.37%) had abnormal ECG including rate abnormality in 13.2%, conduction defects in 12.3%, ischemic changes in 10.5%, and structural defects in 11.4%. Eighty-seven percent of patients had non-dilating pupils and iris atrophy, 13.2% had zonular dialysis and intraoperatively, 78% had capsulorhexis extension, 49.12% had difficult nucleus prolapse, and 28.95% had posterior capsular rent. Conclusion This study highlights the significantly elevated parameters of systemic vascular diseases in PEX patients, like elevated blood pressure and more frequent cardiac anomalies, emphasizing the need for comprehensive systemic evaluation and careful preoperative assessment for ocular comorbidities.