Special needs patients often require specific dental treatments and modified restorative materials that reduce clinical discomfort. Starting from glass ionomer cements (GICs), some different fillers were added to improve their mechanical and clinical performances. The effect of nanohydroxyapatite, antibiotic, and mucosal defensive agent on the mechanical and thermal properties of GICs was investigated. Compressive tests, calorimetric analysis, and morphological investigation were conducted. The middle percentages of fillers increased the elastic modulus while the highest decreases are recorded for highest percentages. Filler and environment also influence the compressive strengths and toughness. The introduction of fillers led to a reduction of the enthalpy with a maximum decrease with the middle percentage. The morphological characterization showed a good dispersion of the fillers. The filler percentages should be selected with a compromise between the elastic modulus, the compressive strength, and the curing time. Obtaining new materials with good clinical and mechanical properties can represent an innovative aspect of this work with positive implication in clinical practice, mainly in uncollaborative patients in which the use of traditional protocols is problematic.