Objective: The purpose of this study was to evaluate the effects of different pediatric drugs and toothbrushing on color changes of restorative materials used in pediatric dentistry. Materials and Methods: Sixty specimens were prepared from each of three restorative materials (compomer [Dyract XP], glass hybrid [Equia Forte], and glass carbomer [GCP Glass Fill]). Specimens were divided into six solution groups (n = 10) and immersed in five different pediatric drugs (antibiotic, analgesic, common cold syrup, cough syrup, and an iron and vitamin formula) and distilled water. Two subgroups (brushed and unbrushed) were established for each group (n = 5). Specimens were agitated for 1 min every 8 h over 2 weeks. Color changes [CIEDE2000 (Delta E00)] were calculated at baseline, 7, and 14 days. Data were subjected to 4-factor mixed-design ANOVA using a general linear model procedure for repeated measurements. Results: After 14 days, the highest Delta E00was found in the compomer/non-brushing group immersed in iron and vitamin formula (5.6 +/- 0.27), and the lowest was in glass hybrid/brushing group immersed in distilled water (0.59 +/- 0.8) pairwise. Delta E00values were significantly greater for compomer than for glass hybrid or glass carbomer (P < 0.05). There were statistically significant differences between the brushing and non-brushing groups for all tested solutions on the compomer specimens (except antibiotic) and glass hybrid specimens (except antibiotic and cough syrup). The Delta 00 values in brushing groups were significantly lower statistically than in non-brushing groups (P < 0.05). Conclusions: Toothbrushing dramatically affected the color stability of the aesthetic restorative materials. The content of pediatric drugs is also an important factor for color change. Glass hybrids and glass carbomers used with their surface sealants appeared to be more resistant to staining from pediatric drug formulations than compomers.