<p>Ibuprofen arginine, a salt form of ibuprofen that combines the widely used nonsteroidal anti-inflammatory drug (NSAID) with L-arginine, was developed to enhance ibuprofen gastrointestinal (GI) absorption. There is evidence that it may also improve its safety profile. This formulation ensures rapid dissolution of ibuprofen in the GI tract, providing rapid and effective pain relief, while simultaneously delivering L-arginine, a substrate for nitric oxide (NO) synthesis. NO is a small molecule that plays a crucial role in various physiological processes in the human body and has been found to be essential for maintaining GI and cardiovascular (CV) homeostasis. Thus, the L-arginine component contributes to the regulation of biological functions and may also help to reduce potential GI and CV events commonly associated with traditional ibuprofen formulations. This narrative review aims to evaluate the clinical safety of ibuprofen arginine, explore the potential mechanisms through which L-arginine may enhance the tolerability of ibuprofen, and situate these findings within the broader context of general safety considerations for NSAIDs, with a particular focus on ibuprofen.</p>