Antimicrobial resistance is a significant global health challenge, with Klebsiella pneumoniae being one of the most common antibiotic-resistant pathogens. This study provides an in-depth analysis of the prevalence and resistance patterns of antibiotic-resistant Klebsiella pneumoniae in the General Hospital of Corfu, Greece, between 2019 and 2022, with the aim of understanding the potential impact of the COVID-19 pandemic on the epidemiology of this bacterium. Utilizing a retrospective epidemiological approach, this study analyzed 212 isolates obtained from the hospital’s Microbiology Department. These isolates were subjected to genotypic and phenotypic identification, with resistance genes (bla-KPC, bla-NDM, bla-VIM, bla-OXA-48, and mcr-1) and antibiotic resistance patterns as the primary focus. The results revealed a significant shift in resistance gene prevalence, with a notable increase in bla-KPC from 16.67% in 2021 to 58.46% in 2022, and a decrease in bla-NDM from 81.48% in 2021 to 38.46% in 2022. In terms of antibiotic resistance patterns, there was a consistent increase in resistance to amikacin and a significant decrease in resistance to ceftazidime/avibactam. These findings underscore the dynamic nature of carbapenem-resistant Klebsiella pneumoniae (CRKP) resistance and highlight the need for ongoing surveillance and adaptive therapeutic strategies in the face of evolving resistance patterns.