Ibuprofen, a common over-the-counter drug, is taken worldwide to alleviate pain and reduce inflammation. While the recommended dosage is generally regarded as safe for consumption, complications arise when the drug is taken chronically, even in the prescribed quantities. Previous research suggests that ibuprofen alters the productivity of various signal transduction pathways throughout the body and stimulates the production of reactive oxygen species (ROS) in liver tissue. Our research aimed to determine if proteins involved in proteolysis and energy producing pathways were altered in cardiac tissue as a result of ibuprofen usage. The study involved eight nine-week-old female mice divided into two treatment groups: control and ibuprofen. Female control mice received pure water while female ibuprofen mice received 100 mg/kg of ibuprofen in water daily for one week before euthanization. The ibuprofen used corresponds to less than 500 mg ibuprofen/day in humans. Heart samples removed from euthanized mice were homogenized, labeled with Tandem Mass Tags (TMT), and then analyzed by liquid chromatography-tandem Mass Spectrometry (MS). Spectral analysis yielded 120 proteins that were altered in a statistically significant manner (p ≤ 0.0028 according to the Benjamini-Hochberg procedure). Pathway analysis conducted on statistically significantly altered proteins suggests moderate ibuprofen consumption results in changes in aerobic respiration, oxidative stress, the proteasome proteolytic system, the nucleotide metabolic process, and muscle cell development pathways. We conclude that ibuprofen consumption at recommended dosages significantly alters many pathways in cardiac tissue, which may be associated with the clinically observed increased risk of cardiovascular disease for those taking ibuprofen. This research is funded by the NIEHS/Superfund Research Program (P42 ES004699). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.