Abstract Background: Consumption of different types of beverages and liquid drugs can affect of the surface properties of restorative material. This may lead to an increased probability of dental caries and periodontal inflammation. Aim: This study evaluated and compared the effect of amoxicillin suspension (AMS) and azithromycin suspension (AZS) on the surface roughness (SR) of silver-reinforced glass ionomer (SGI) and nano resin-modified glass ionomer (NGI). Material and Methods: Thirty disks (2 mm height × 4 mm diameter) of each glass ionomer (GI) type were prepared and subdivided into three groups (n = 10), which were separately exposed to AMS, AZS, and artificial saliva (AS). SR was evaluated by atomic force microscopy before and after three-immersion protocols repeated over a 3-week duration with 2-day intervals. In each protocol, the GI samples were exposed weekly to AMS three times daily, AZS once daily, and a full day to AS. Results: This study demonstrated, for the first time, the effect of a basic drug (AZS) on the SR of GIs. Intra- and inter-group comparisons showed significant changes (P ˂ 0.05) in the SR pattern of the GIs after immersion cycles in AZS, AMS, and AS. However, the acidic medication (AMS) exhibited significantly higher changes in SGI than in NGI. Conclusions: The SR of NGIs and SGIs can be significantly affected by the use of AMS and AZS suspensions. SGI demonstrated higher SR deterioration than NGI after immersion cycles in AMS.