We assessed the effect of different available denture cleansers on the roughness and hardness of polyetherketoneketone, thermoinjection-molded polyamide, and polymethylmethacrylate. A total of 150 disc-shaped specimens were fabricated (10 mm × 2 mm) from these three denture base resins, and divided into five subgroups ( n = 10) according to immersion procedures. One of these groups subjected to distilled water served as control, whereas other groups were subjected to daily cleansing with four denture cleansers (Corega, Protefix, Curaprox, and Perlodent) for 8 h a day for 140 days. The surface roughness and hardness values of specimens were recorded by measuring twice at baseline, and again after application of chemical solutions. Topography alterations after treatments were assessed with scanning electron microscopy. The data were subjected to statistical analysis and comparison among groups was done using Kruskal Wallis and Wilcoxon Signed Ranks tests. P-value <0.05 was considered significant. The surface roughness of polyetherketoneketone, polymethylmethacrylate, and polyamide dentures was increased significantly by chemical solutions of denture cleansers. While the hardness value of polyetherketoneketone was not affected significantly after immersion in denture cleansers, those of polymethylmethacrylate and polyamide decreased significantly. Compared with Curaprox, the effervescent tablets significantly altered the surface hardness and roughness of polyamide. Denture cleansers can considerably alter the surface roughness and hardness of denture base resins and should be used carefully depending on the material.