<p>Excipients are important inactive components in drug formulations that ensure stability, bioavailability, and patient compliance. However, emerging evidence suggests that certain excipients, once considered inert, can cause hypersensitivity reactions in certain individuals. Such reactions include mild erythema due to systemic anaphylaxis and create clinical challenges that are difficult to handle. This review presents a systematic review of the existing literature on excipient hypersensitivity, with specific attention paid to commonly implicated excipients such as polyethylene glycol (PEG), parabens, and tartrazine. Hypersensitivity mechanisms (immune-mediated [IgE, T-cell] and non-immune) are discussed, along with their clinical features and diagnostic challenges. In addition, geographic variations in reporting are discussed, which in turn focus on the role of pharmacovigilance in the reduction of risk. Geographic variations in excipient hypersensitivity reporting are also discussed, highlighting disparities in pharmacovigilance efforts across different regions. This review also discusses recent work, regulatory issues, and desensitization protocols for the control of hypersensitivity reactions. Persistent surveillance and individual strategies are needed to enhance patient safety in the context of excipient-induced hypersensitivity.</p>