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This study presented two 360° nature videos in a VR headset to assess stress reduction and mood enhancement of people in isolation. Objective measures of stress such as electrodermal activity (EDA) and heart rate variability (HRV) were collected and subjective measures of mood were compared for two 15-minute 360/VR nature scenes and an indoor control scene. Natural scenes reduced stress and negative affect and improved mood and scene perception, indicating VR’s potential for upliftment in isolated settings. Preference for VR scene content had a significant effect on subjective responses to the scenes, and measures of subjective preference suggest the need to provide a variety of content in isolation and confinement.