(1) Background: The intra-oral behavior of clear thermoplastic dental materials can be influenced by various intrinsic and extrinsic factors. Aim: The purpose of this in vitro study was to evaluate the optical properties, color changes and whiteness variations of four thermoplastic polymers used for dental appliances, in a simulated oral environment. (2) Methods: Customized thermoformed specimens of four PETG thermoplastics were selected and investigated in this study: Leone [L], Duran [D], Erkodur [E] and Crystal [C]. The thermoplastic samples were divided into three groups related to pH values (neutral, acidic and basic). A period of 14 days was simulated. Five stages resulted: I. dessicated specimens; II. hydrated in artificial saliva; III. subsequent desiccated; IV. artificial aged; V. further dessicated. Optical CIE L*a*b* coordinates were determined and optical properties, like TP (translucency), OP (opalescence) values, color differences ΔE-NBS, white indexes in dentistry WID and white index differences ΔWID were calculated for all stages of the study, for each group of the materials. Statistical analyses were performed. (3) Results: Optical properties of PETG clear thermoplastic materials, like TP and OP, increase in a simulated oral environment and the changes become significant after artificial aging. Related to pH values, the optical behavior between the materials is significantly different. During artificial aging, the tested materials behave significantly differently in terms of optical properties. (4) Conclusions: After the simulated period of 14 days, TP and OP values increase, with a migration of the color towards red and yellow. Color changes in some cases even reach the level of extremely marked. Whiteness increases, and the differences are mostly perceptible, but partially exceed the limit of acceptability.