Background: Antibiotics and none-steroidal anti-inflammatory drugs are often taken orally to treat human diseases. The use of these drugs adversely could affect the natural oral microbiota composition and oral immune system. In the meanwhile, it may break the original balance of oral micro-ecosystem. Exploring this change is of great importance to host health. Methods: In this study, we took 20 SD rats and divided them into four groups of five rats each. Each of these groups was administered specified doses of amoxicillin (AMX), ornidazole (ORD), aspirin (ASP), or purified water (CTR), using oral gavage daily for 14 days. High-throughput sequencing was used to investigate the microbiota difference in the four groups of rats once the oral gavage completed. ELISA kit was used to determine IgG and SIgA content, to understand the effect of the drugs on the oral immune system. Results: We found that oral bacterial composition, IgG and sIgA were significantly affected by the use of these drugs. No matter which medication the rats takes, oral microbiota diversity increase significantly. At the genus level, The Lactobacillaceae, which is essential to the human food digest, raised in the aspirin take group. Staphylococcus and Pasteurella increased in the ornidazole group. Klebsiella, Corynebacterium rose significantly in the amoxicillin group. In normal oral cavity without taking the task medicine, Streptococcus, Pasteurella, and Rothia were in a relatively high abundance. IgG and SIgA content also changed by using these drugs, thus indicating applied those drugs impact of the oral immune system. Conclusion: Our results indicate that antibiotic and none-steroidal anti-inflammatory drugs could influence the oral microbiota composition, which could also destroy the original oral micro-ecosystem environment. The non-antibiotic drug effect on the oral microbiota and oral immune system similar to the antibiotic drug. All these changes may have a negative influence on host health. (C) 2018 Elsevier Inc. All rights reserved.