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Antibiotic resistance can be considered one of the major bacterial pathogenesis factors, and its increase is an important public health concern. Among resistant bacteria, staphylococci can express high levels of resistance, representing some of the most common human pathogens that are important causes of infection at any level. This paper aims to assess the burden of staphylococcal infections, in light of the growing phenomenon of antibiotic resistance, in a high-risk hospital setting. We carried out a cross-sectional study on data obtained from clinical specimens from an Italian healthcare facility particularly specialised in orthopaedics and traumatology. Specifically, we evaluated the trends in the Staphylococcus spp. detection rates and antibiotic resistance in the ten-year period of 2012-2024. The number of specimens increased over time but remarkably decreased during the COVID-19 pandemic. Despite this, the detection rate of Staphylococcus spp. remained quite constant, confirming the common circulation of these pathogens in such nosocomial environments. Antibiotic resistance concomitantly decreased, but a novel increase was found in recent years. Our findings highlight the importance of continuous monitoring of the antibiotic resistance rates of staphylococci due to the importance of these pathogens in human pathology and their ability to cause life-threatening antibiotic-resistant infections.