Research shows that reduced exposure to natural contexts is associated with an increase in psychophysical disorders. Recent evidence suggests that even a brief experience in natural scenarios can positively affect people's health and well-being. However, natural contexts are not always easily accessible. This study investigates the effects of natural and indoor virtual environments (VREs) on psychophysiological and cognitive responses. Following a within-subject design, 34 healthy participants were exposed to two VREs (i.e., a forest and a living room) in a counterbalanced order through a head-mounted display (Oculus Rift). Participants were asked to explore the scenarios and execute a modified version of the Paced Auditory Serial Addition Test. Physiological parameters (heart rate, skin conductance level [SCL], and respiration rate) were recorded during the whole session. After the exposure to VREs, participants filled a set of visual analog scales to rate their subjective experience of presence, relaxation, and stress. Participants reported a higher perceived sense of relaxation in the virtual forest. Moreover, their SCLs were significantly higher in this environment, showing that the forest elicited higher physiological arousal than the living room. Furthermore, their SCLs were significantly higher during the attentional task in the virtual living room. The results suggest that a natural virtual environment can make people feel more relaxed and physiologically engaged than an indoor scenario. The latter instead can be linked to a performing venue, as reported for real contexts. However, these changes were not related to modulations of attentional performance. Copyright © 2022, Mary Ann Liebert, Inc.