Aim/objective <p>This study explored the impact of evidence-based nursing management strategies on quality of life (QoL) among Saudi patients with chronic kidney disease (CKD) and cardio-renal-metabolic (CKM) comorbidities.</p> Background <p>CKD poses a significant health burden in Saudi Arabia, often compounded by CKM comorbidities such as hypertension and diabetes. Nurse-led interventions are critical in promoting adherence to management strategies, yet limited evidence exists on their effect within this population.</p> Design <p>A cross-sectional quantitative study was conducted among 285 adult CKD patients (stages 3–5).</p> Methods <p>Participants completed a validated questionnaire assessing adherence to management strategies (medication, diet, self-monitoring, education, and physical activity) and QoL using the Kidney Disease Quality of Life instrument. Regression modeling identified predictors of QoL.</p> Results <p>Adherence to management strategies explained 46.5% of the variance in QoL scores (R² = 0.465, β = 0.682, <i>p</i> &lt; 0.001). Patients with high adherence scored 0.43 points higher on the KDQOL scale compared with low-adherence peers. Medication adherence was highest (81.5%), while physical activity adherence was lowest (58.9%). QoL declined progressively with longer CKD duration (3.91 at &lt; 1 year vs. 3.45 at &gt; 5 years, <i>p</i> = 0.003).</p> Conclusions <p>Nurse-led, evidence-based management strategies significantly improve QoL among Saudi CKD patients with CKM comorbidities. Early, culturally tailored interventions are essential to address low adherence in areas such as physical activity.</p> Clinical trial number <p>Not applicable.</p>