Abstract Purpose To assess the impact of different electronic relaxation devices on common stressful patient symptoms experienced in intensive care unit (ICU). Methods Sixty critically ill patients were enrolled in four relaxation sessions using a randomized cross-over design: standard relaxation (TV/radio), music therapy (MUSIC-CARE©), and two virtual reality systems using either real motion pictures (DEEPSEN©) or synthetic motion pictures (HEALTHY-MIND©). The goal was to determine which device was the best to reduce overall patient discomfort intensity (0–10 Numeric Rating Scale (NRS); primary endpoint). Secondary endpoints were specific stressful symptoms (pain, anxiety, dyspnea, thirst, and lack of rest feeling) and stress response measured by Analgesia/Nociception Index (ANI). Multivariate mixed-effect analysis was used, taking into account patient characteristics and multiple measurements. Results Fifty patients followed the full research protocol, and ten patients did at least one research planned session of relaxation. HEALTHY-MIND© was associated with a significant decrease in overall discomfort, the primary endpoint (median NRS = 4[2–6] vs. 2[0–5]; p = 0.01, mixed-effect model), accompanied by a significant decrease in stress response (increase in ANI, secondary endpoint; p < 0.01). Regarding other secondary endpoints, each of the two virtual reality systems was associated with a decrease in anxiety ( p < 0.01), while HEALTHY-MIND© was associated also with a decrease in pain ( p = 0.001) and DEEPSEN© with a decrease in lack of rest ( p = 0.01). Three incidents (claustrophobia/dyspnea/agitation) were reported among 109 virtual reality sessions. Cybersickness was rare (NRS = 0[0–0]). Conclusion Electronic relaxation therapy is a promising, safe, and effective non-pharmacological solution that can be used to improve overall discomfort in alert and non-delirious ICU patients. Its effectiveness depends on technical characteristics (virtual reality using a synthetic imagined world versus a real world or music therapy alone without virtual reality), as well as the type of symptoms.