The effect of printing parameters on the surface characteristics of three-dimensional (3D)-printed denture base resins (DBRs) is neglected. Therefore, this study investigated the effect of printing orientation and post-curing time on the surface roughness and hardness. One conventional heat-polymerized (HP) resin and two 3D-printing resins (NextDent (ND) and ASIGA (AS)) were used to fabricate a total of 250-disc (10 × 2.5 mm) specimens. ND and AS specimens were printed with different orientations (0-, 45-, and 90-degree) and each orientation group was subjected to four post-curing times (30, 60, 90, 120 min). Printed specimens were thermo-cycled (10,000 cycles) followed by the measuring of surface roughness (Profilometer (Ra)) and hardness (a Vickers hardness (VH)). ANOVA and post hoc tests were used for data analysis (α = 0.05) at significant levels. AS and ND showed no significant changes in Ra when compared with HP (p ˃ 0.05), except the 45-degree orientation (AS/90 min and AS/120 min) significantly increased surface roughness (p ˂ 0.001). There was no significant difference in Ra with different orientations and post-curing time for both materials AS and ND (p ˃ 0.05). Compared with HP, 3D-printed DBRs showed low VH values (p ˂ 0.001). For AS, 90-degree orientation showed a significant decrease in VH at 60, 90, and 120 min when compared with 0- and 45-degree orientation (p ˂ 0.001), while ND showed no significant difference in VH with different printing orientations (p ˃ 0.05). The VH of AS and ND improved when increasing post-curing time to 120 min (p ˂ 0.001), and the printing orientations and post-curing time did not affect the Ra of 3D-printed DBRs.