Background <p>Hyperglycemia is frequently observed in critically ill patients and is linked to increased complications, prolonged ICU stays, and higher mortality. Traditional physician-led insulin management may lack the responsiveness required for optimal glycemic control. In contrast, nurse-led insulin infusion protocols offer a more timely and effective approach in the ICU setting.</p> Aim <p>This study evaluated the effectiveness of a nurse-led insulin infusion protocol in managing hyperglycemia among critically ill patients compared to conventional physician-directed care.</p> Methods <p>A quasi-experimental design was implemented in the ICU of Fayoum University Hospital, Egypt, from January to June 2024. A total of 80 adult patients with hyperglycemia were randomly assigned to either a nurse-led insulin infusion protocol group (n = 40) or a standard care group (n = 40). Key outcomes included time to achieve target blood glucose (BG) levels (110–149&#xa0;mg/dl), frequency of BG monitoring, and ICU length of stay. Data were analyzed using SPSS software.</p> Results <p>Patients in the intervention group achieved significantly better glycemic control at all five time points (<i>p</i> &lt; 0.001), with 62.5% reaching target BG levels within 1–2&#xa0;days compared to 12.5% in the control group. Additionally, 52.5% of intervention patients had ICU stays of 3–4&#xa0;days, whereas the same proportion in the control group stayed for more than 7&#xa0;days (<i>p</i> &lt; 0.001). The frequency of BG monitoring was also higher in the intervention group.</p> Conclusion <p>The nurse-led insulin infusion protocol significantly enhanced glycemic control and reduced ICU stay duration. These findings support integrating nurse-led protocols in ICU settings to improve patient outcomes, ensure timely interventions, and optimize resource utilization.</p> Trial registration <p>Pan African Clinical Trials Registry (PACTR), no: PACTR202506863203683, date of approval 04/06/2025.</p>