Beta-lactam antibiotics are essential components in the current antimicrobial treatment strategy, playing a crucial role in ambulatory patients and hospitalized patients. Despite their prominent therapeutic index, the use of beta-lactam can lead to adverse effects, with allergic reactions being the most concerning because of their severity. Additionally, the phenomenon of cross-reactivity may occur among various beta-lactam families, with side chains significantly contributing to immunological recognition, making these structures often responsible for the cross-allergic reactivity of beta-lactams. Tools to assess beta-lactam allergy include taking a patient's medical history, performing skin tests, and conducting provocation tests. This research aims to analyze the relevant aspects related to the safe administration of beta-lactam antibiotics in hospitalized patients as well as provide knowledge on the proper management of patients with such hypersensitivity, by doing systemic research. This research was made using Google Scholar and keywords such as "Beta-lactam allergy,” "Hypersensitivity,” "Cross-reactivity,” "Desensitization,” and “Beta-lactam allergy management.” In conclusion, substituting a beta-lactam antibiotic with an alternative antibiotic may not always be the best management option for these patients, as it may lead to more adverse effects, be less effective, and prolong hospitalization time. It may also result in higher rates of antibiotic-resistant infections and increased medical costs, as these alternatives are often more expensive. However, an alternative within the beta-lactam family can be sought by conducting the appropriate analyses. Although cross-reactivity does not always occur among all beta-lactams, potential cross-reactivity should always be considered.