The development of sustainable and safe strategies to protect the environment and human health from the harmful effect of metals has become an issue of great concern for the scientific community. Aluminium is abundant in nature but with low bioavailability, under normal environmental conditions. However, acid rains and the extensive employment of this metal in different fields could provoke its release in significant concentrations in various environmental and biological compartments, with a possible depletion or replacement of nutrients and essential metal cations, such as Ca2+ and Mg2+. A previous study demonstrated a very good affinity of five 3-hydroxy-4-pyridinone (3,4-HP) ligands towards Al3+. To confirm their potential for practical applications, an in-depth thermodynamic study was performed to ascertain if, beside their sequestering capability towards the M3+, there could be a possible depletion of Ca2+ and Mg2+. The M2+/(3,4-HP) complexation was investigated at 0.15 ≤ I/mol L−1 ≤ 1.00 and 288.15 ≤ T/K ≤ 310.15 in NaCl(aq), obtaining information on speciation models, stability constants and thermodynamic parameters dependence on ionic strength and temperature. Furthermore, the ligands sequestering ability towards Ca2+ and Mg2+ was evaluated calculating the pL0.5 parameter (total concentration of ligand required to remove 50% of metal in trace). A comparison among the obtained data with those already reported in literature for Al3+/(3,4-HP) systems, showed that, from the thermodynamic point of view, no competition between Ca2+/Mg2+ and Al3+ should occur since the ligands under study promote the M3+ removal from the human body, but hindering the possibility of essential metals depletion.