Background: Ultrasonographic optic nerve sheath diameter (ONSD) is a satisfactory noninvasive intracranial pressure (ICP) monitoring test. Our aim was to evaluate ONSD as an objective screening tool to predict and diagnose ICP changes early in sepsis-associated encephalopathy (SAE). Methods: Our prospective observational study was conducted on patients with sepsis, and after intensive care unit (ICU) admission, the time to diagnose SAE was recorded, and patients were divided into a non-SAE group including conscious patients with sepsis and a SAE group including patients with sepsis with acute onset of disturbed conscious level. ONSD was measured within 24 h of ICU admission for all patients and then every other day for up to 10 consecutive days until ICU discharge or death. The primary outcome was to compare ONSD measurements of both groups to find if there was a correlation between ONSD and SAE occurrence. Results: Eighty-nine patients with sepsis were divided into a non-SAE group (n = 45) and an SAE group (n = 44). ONSD showed a statistically significant difference at day 0 and a highly significant difference at days 2, 4, 6, 8, and 10. Day 2 ONSD had the best accuracy for predicting SAE, with a cutoff > 5.2 mm (sensitivity of 93.2%, specificity of 100%), a statistically positive correlation with the Sequential Organ Failure Assessment score (r = 0.485, P < 0.001) and ICU length of stay (r = 0.238, P < 0.001), and a statistically significant wider in patients who died compared to those who survived (P < 0.001). Conclusions: ONSD could be an objective screening method for early diagnosis of SAE, with a cutoff > 5.2 mm.