Purpose <p>The longevity of computer-aided design and computer-aided manufacturing (CAD/CAM) lithium disilicate-based restoration varies significantly depending on the type of restoration, the properties of materials used, and their esthetics. This study investigated the effect of multiple firings on flexural strength, microhardness, bond strength, and color stability of different CAD/CAM lithium disilicate-based glass ceramics.</p> Materials and methods <p>Three different lithium disilicate-based glass ceramics, IPS e.max CAD (EM), CEREC Tessera (CT), and LiSi CAD (LC) were wet-sectioned into rectangular (approximately 14.5 × 12.4 × 1.2 mm³). Specimens (<i>n</i> = 180 per material) were randomly divided into five subgroups according to the number of firings (1, 2, 3, 4, and 5) (<i>n</i> = 36 per subgroup). Color stability was investigated using CIEDE2000 (<InlineEquation ID="IEq1"> <EquationSource Format="TEX">\(\triangle{\mathrm E}_{00}\)</EquationSource> </InlineEquation>), followed by biaxial flexural strength test (<i>n</i> = 10 per subgroup). The specimens were tested for microhardness (<i>n</i> = 10 per subgroup). In addition, the specimens were bonded with Panavia™ SA. The shear bond strength was performed using a universal testing machine (<i>n</i> = 16 per subgroup). The fracture surfaces were examined under stereomicroscopy. Data was analyzed by a two-way ANOVA with Tukey’s adjustment for multiple comparisons (<InlineEquation ID="IEq2"> <EquationSource Format="TEX">\(\:\alpha\:\)</EquationSource> </InlineEquation>=0.05).</p> Results <p>According to the 2-way ANOVA, the color stability was significantly influenced by both materials and number of firing cycles. The color stability of LC statistically significant increased upon increasing the number of firings (<i>p</i> &lt; 0.0001). In addition, a significant between materials and number of firings was also observed (<i>p</i> &lt; 0.0001). There was no apparent impact on the biaxial flexural strength and microhardness from multiple firings (<i>p</i> &gt; 0.05). However, EM exhibited the highest biaxial flexural strength, while LC showed the highest microhardness, regarding to the materials (<i>p</i> &lt; 0.0001). For shear bond strength, material (<i>p</i> &lt; 0.001) and number of firings (<i>p</i> = 0.0277) were found significant, specifically LiSi CAD.</p> Conclusion <p>There was no apparent impact on biaxial flexural strength and microhardness of CAD/CAM lithium disilicate-based glass ceramics after multiple firings. However, multiple firings affected the color stability and shear bond strength of lithium disilicate-based glass ceramics. The color change was noticeable after the third firing cycle, specifically CEREC Tessera. The shear bond strength of LiSi CAD increased as a function of multiple firings. Cautiously corrective adjustments and recontouring are required to minimize the unessential firings.</p>