Background <p>Excessive screen time is associated with psychological distress and physiological dysregulation. We evaluated a 2-week digital detox in medical students, focusing on key outcomes: cortisol, C-reactive protein (CRP), interleukin-6 (IL-6), heart-rate variability (HRV), and psychometrics (Perceived Stress Scale [PSS], Generalized Anxiety Disorder-7 [GAD-7]).</p> Methods <p>In a randomized three-group trial at two medical colleges, participants were allocated 1:1:1 to (i) detox + alternative activities, (ii) screen-time reduction only, or (iii) control. Randomization used stratified block procedures (campus × academic year × gender). We employed a convergent parallel mixed-methods approach, collecting qualitative feedback alongside quantitative measures, and integrating at interpretation. Compliance was tracked via device-level analytics and daily logs. Pre- and post-assessments included HRV, morning cortisol, CRP, IL-6, blood pressure, pulse, and PSS/GAD-7. “Alternative activities” were brief, low-cost options (mindfulness/breathing, brisk walking, journaling, in-person peer time), with ≥ 2 modalities per participant.</p> Results <p>The detox + activities group showed the largest improvements across biomarkers, HRV, and psychometric scores; the reduction-only group showed moderate improvements, while the control group exhibited no significant change. Beyond statistical significance, practical significance was observed: psychometric scores shifted across standard clinical categories (e.g., PSS high to moderate; GAD-7 moderate to mild), HRV increases indicated greater overall heart-rate variability and improved autonomic balance, and modest blood-pressure changes reflected favorable autonomic balance. Qualitative themes (e.g., mental reset, regaining academic control, reconnecting offline) converged with these changes.</p> Conclusion <p>A structured, low-cost 2-week digital detox, particularly when paired with alternative activities, was associated with psychological well-being and key physiological markers in medical students. Limitations include the short intervention duration, two-site sample, reliance on self-report/app analytics for compliance, and absence of blinding. Digital-use hygiene paired with brief offline activities may offer a scalable student well-being strategy, especially in resource-limited settings; multi-site factorial trials with longer follow-up are warranted.</p> Trial registration <p>Clinical trial number not applicable.</p>