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Objectives: This paper aims to explore the factors influencing the spatial cognition of the visually impaired in familiar environments. Background: Massage hospitals are some of the few places that can provide work for the visually impaired in China. Studying the spatial cognition of the visually impaired in a massage hospital could be instructive for the design of working environments for the visually impaired and other workplaces in the future. Methods: First, the subjective spatial cognition of the visually impaired was evaluated by object layout tasks for describing the spatial relationships among object parts. Second, physiological monitoring signal data, including the electrodermal activity, heart rate variability, and electroencephalography, were collected while the visually impaired doctors walked along prescribed routes based on the feature analysis of the physical environment in the hospital, and then their physiological monitoring signal data for each route were compared. The visual factors, physical environmental factors, and human–environment interactive factors that significantly impact the spatial cognition of visually impaired people were discussed. Conclusions: (1) visual acuity affects the spatial cognition of the visually impaired in familiar environments; (2) the spatial cognition of the visually impaired can be promoted by a longer staying time and the more regular sequence of a physical environment; (3) the spatial comfort of the visually impaired can be improved by increasing the amount of greenery; and (4) the visual comfort of the visually impaired can be reduced by rich interior colors and contrasting lattice floor tiles.