The global dynamics of the flow of energetic particles through the Martian upper atmosphere is studied for different cases reflecting variations in solar cycle, seasons, and epochs over history. In this study, the combination of the new 3-D Direct Simulation Monte Carlo kinetic model and the modern 3-D Mars Thermosphere General Circulation Model is employed to describe self-consistently the Martian upper atmosphere (i.e., the thermosphere/ionosphere and the exosphere). The variations in the Martian upper atmosphere over long-term (seasons and solar cycle) and evolutionary (Martian history) time scales are presented and discussed using the equinox solar low case extensively described in the work of Valeille et al. (2009c) as reference throughout. These characteristic conditions lead to significant variations in the thermosphere/ionosphere temperatures, dynamical heating, winds, and ion/neutral density distributions, which, in turn, affect the exosphere general structure, the hot corona shape, and the escape rate and have important implications for the study of the ion loss, atmospheric sputtering, and interaction with the solar wind in general. Calculations for present conditions are performed for three characteristic seasons (aphelion, equinox, and perihelion), while solar activity is either fixed to low or high conditions. Calculations for past conditions are related to a solar EUV flux enhancement of 1, 3, and 6 times the present values. Spatial-, seasonal-, solar cycle–, and evolutionary-driven variations, although exhibiting very different time scales, are all shown to exert an influence of the same order. Models of Mars upper atmosphere should address them accordingly.