In this paper, we show that the complex geological evolution of Valles Marineris, Mars, has been highly influenced by the manifestation of magmatism (e.g., possible plume activity). This is based on a diversity of evidence, reported here, for the central part, Melas Chasma, and nearby regions, including uplift, loss of huge volumes of material, flexure, volcanism, and possible hydrothermal and endogenic-induced outflow channel activity. Observations include: (1) the identification of a new > 50 km-diameter caldera/vent-like feature on the southwest flank of Melas, which is spatially associated with a previously identified center of tectonic activity using Viking data; (2) a prominent topographic rise at the central part of Valles Marineris, which includes Melas Chasma, interpreted to mark an uplift, consistent with faults that are radial and concentric about it; (3) HiRISE-identified landforms along the floor of the southeast part of Melas Chasma that are interpreted to reveal a volcanic field; (4) CRISM identification of sulfate-rich outcrops, which could be indicative of hydrothermal deposits; (5) GRS K/Th signature interpreted as water–magma interactions and/or variations in rock composition; and (6) geophysical evidence that may indicate partial compensation of the canyon and/or higher density intrusives beneath it. Long-term magma, tectonic, and water interactions (Late Noachian into the Amazonian), albeit intermittent, point to an elevated life potential, and thus Valles Marineris is considered a prime target for future life detection missions.