OBJECTIVE To compare flexural strength, elastic modulus, and surface hardness of computer aided design and computer aided manufacturing CAD-CAM milled, 3D-printed, and heat-polymerized denture base resins. METHODS A total of 120 specimens were fabricated from heat-polymerized acrylic resin (HP), milled resin (Avadent and IvoCad), and 3D-printed resin (ASIGA, FormLabs, and NextDent). The specimens were divided into 6 groups according to the type of denture base material (n = 20/material) (10/flexural properties and 10/hardness). Flexural strength and elastic modulus of the specimens were evaluated by 3-point bending test and surface hardness by Vickers hardness test. To test flexural properties, the specimens were fabricated according to ISO 20795-1:2013 standards (64 × 10 × 3.3 ± 0.2 mm). The dimensions for hardness test were 15 × 10 × 2.5 ± 0.2 mm. Scanning electron microscope was used to evaluate the surface morphology of the fractured specimens. The means and standard deviations were calculated, followed by one-way ANOVA and Tukey post-hoc test (α = 0.05). RESULTS Milled resins showed significantly higher values for flexural strength, elastic modulus, and surface hardness, followed by HP and then 3D-printed resins (p < 0.001). Within milled groups, flexural strength of AvaDent was significantly higher than IvoCad (p < 0.001), while elastic modulus and hardness didn't show significant difference. Within 3D-printed resins, ASIGA showed the highest flexural strength and elastic modulus, insignificantly with FormLabs (p = 0.595) and significantly with NextDent (p = 0.008). ASIGA also showed significantly the highest hardness among the 3D-printed groups. No significant difference was found between FormLabs and NextDent in flexural strength (p = 0.357), elastic modulus (p = 1.00), or surface hardness (p = 0.987). CONCLUSIONS CAD-CAM milled resins had greater flexural properties and hardness compared to heat-polymerized acrylic resin and 3D-printed resins. Although 3D-printed samples showed the lowest values of tested properties, the flexural strength and modulus were above clinically acceptable values.