This paper reports on the results of an empirical evaluation that aimed to define the effectiveness and efficiency of different visual variables in depicting the Space–Time Cube’s (STC) content. Existing STC applications demonstrate that the most used visual variables are size and colour hue. Less is known, however, about their usability metrics. The research sets design criteria for STC contents, such as space–time paths, based on the cartographic design theory. The visual variables colour hue, colour value, colour saturation, size and orientation have been applied in two different use case studies. Besides, to support the three-dimensional visual environment, depth cues such as shading and transparency were considered too. User tests have been executed based on real-world problems with particular attention for the visualization strategy and data complexity. The outcomes revealed the most efficient and effective visual variables to represent data of various complexities in the STC.