Dental polymers are now available as monolithic materials which can be readily used in computer-aided design and computer-aided manufacturing (CAD/CAM) systems. Despite possessing numerous advantages over conventionally produced polymers, the polymers produced by either of these systems fail to exhibit immunity to surface microbial adhesion when introduced into the oral environment, leading to the development of oral diseases. The aim of this study was to analyze the biofilm formation of six microorganisms from the oral cavity and its correlation to the surface characteristics of CAD/CAM dental polymers. A total of ninety specimens were divided into three groups: resin-based composite, polymethyl methacrylate, and polyether ether ketone. The experimental procedure included surface roughness and water contact angle measurements, colony forming unit counting, and scanning electron microscopy analysis of biofilm formed on the surface of the tested materials. The data were analyzed using the Kruskal–Wallis test, with a Dunn’s post hoc analysis, and one way analysis of variance, with a Tukey’s post hoc test; the correlation between the measurements was tested using Spearman’s correlation coefficient, and descriptive statistics were used to present the data. Despite using the same manufacturing procedure, as well as the identical manufacturer’s finishing and polishing protocols, CAD/CAM dental polymers revealed significant differences in surface roughness and water contact angle, and the increased values of both parameters led to an increase in biofilm formation on the surface of the materials. The CAD/CAM resin-based composite showed the lowest number of adhered microorganisms compared to CAD/CAM polymethyl methacrylate and CAD/CAM polyether ether ketone.