Background <p>Mental health disorders, including depression, anxiety, and pain, are prevalent among ambulatory patients. Nurse-Led Education and Telehealth interventions have emerged as promising approaches to improving mental health outcomes. However, their comparative effectiveness remains unclear, particularly in Saudi Arabia.</p> Aim <p>This study compares the impact of Nurse-Led Education and Telehealth interventions on mental health outcomes (depression, anxiety, and pain) for ambulatory patients in Saudi Arabia.</p> Methods <p>A quasi-expremintal study with pre and post tests were conducted with 400 participants, who were recruited through purposive sampling and assigned to receive either Nurse-Led Education or Telehealth interventions over eight weeks. Depression, anxiety, and pain were measured using the PHQ-9, STAI, and VAS tools, respectively. Data were analyzed using descriptive statistics, independent t-tests, logistic regression, and Structural Equation Modeling (SEM), with anxiety examined as a potential mediator.</p> Results <p>Both the Nurse-Led Education and Telehealth Intervention groups showed significant improvements in mental health outcomes, including reductions in depression (PHQ-9), anxiety (STAI), and pain (VAS). The Nurse-Led Education group improved from 20.3 to 12.4 in PHQ-9, while the Telehealth group decreased from 21.8 to 15.2, both with <i>p</i> &lt; 0.001. Pain scores also decreased significantly in both groups, with the Nurse-Led group improving from 18.9 to 9.3 and the Telehealth group from 31.3 to 18.5 (<i>p</i> &lt; 0.001). Anxiety levels decreased in both groups (<i>p</i> &lt; 0.001). Regression analysis indicated that Telehealth had a stronger association with improvements across all outcomes, with anxiety playing a significant mediating role in the Telehealth group. Structural Equation Modeling (SEM) further demonstrated that Telehealth had a more pronounced effect on pain management and mental health outcomes, highlighting its potential for more robust results compared to Nurse-Led Education, though both interventions proved beneficial.</p> Conclusion <p>Telehealth interventions showed superior efficacy in managing depression and pain, potentially due to individualized care. Nurse-Led Education excelled in fostering peer support, which equally benefited anxiety management. These findings highlight the importance of tailored approaches in mental health care.</p> Clinical trial <p>No clinical trial.</p>