Tobacco smoking is a global health hazard that kills about 5 million people annually. Waterpipe smoking is among the most popular methods of tobacco consumption world-wide. In this study, we investigated whether waterpipe smoking impairs learning and memory in the hippocampus, a question of special concern due to the particular popularity of waterpipe use among youth. Additionally, possible molecular targets for expected learning and memory impairment were determined. In this study, rats were exposed to waterpipe smoke (WTS) by whole body exposure 1hr × 5 days/wk, for one month, and outcomes were compared to a control group exposed only to fresh air. Outcomes included spatial learning and memory using the Radial Arm Water Maze (RAWM), and oxidative stress biomarkers (catalase, GPx, SOD, GSH, GSSG, GSH/GSSG ratio). We found that WTS exposure led to impaired short- and long-term memory. This impairment was accompanied by reduced hippocampal activity of catalase, SOD, GPx, GSH, and GSH/GSSG, elevated GSSG, thus, marked changes in oxidative stress biomarkers. In conclusion, there is reason for concern that WTS exposure may impair cognitive ability.