Background: One of the drawbacks of tooth-colored dental restorations is their discoloration over time. The present study aimed to determine the effect of four categories of pediatric medications, including analgesics, antibiotics, anticonvulsants, and multivitamins, on two types of tooth-colored dental materials, namely, composite resins and glass ionomer cements. Materials and Methods: In this in vitro study, a total of 40 specimens with disc shapes (with a diameter of 5 mm and thickness of 2 mm) were prepared from each material and immersed in eight different drugs for 2 min three times a day for 1 week. The values of the baseline color were calculated based on the CIE (International Commission on Illumination) L*a*b* system. After 7 days, ΔE values were calculated. Two-way analysis of variance was employed for statistical analysis. Statistical significance was defined at 0.05. Results: Statistical analysis showed that there were significant differences between ΔE and different restorative materials as well as ΔE and drug types (P < 0.001). Conclusion: According to the results of this in vitro study, all the four types of drugs caused the discoloration in all the restorative materials, and the color change values were affected by the type of used drug and restorative material.