The rise of antibiotic resistance and the dwindling antimicrobial pipeline have emerged as significant threats to public health. The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a global threat, with limited options available for targeted therapy. The CRKP has experienced various changes and discoveries in recent years regarding its frequency, transmission traits, and mechanisms of resistance. In this comprehensive review, we present an in-depth analysis of the global epidemiology of K. pneumoniae, elucidate resistance mechanisms underlying its spread, explore evolutionary dynamics concerning carbapenem-resistant hypervirulent strains as well as KL64 strains of K. pneumoniae, and discuss recent therapeutic advancements and effective control strategies while providing insights into future directions. By going through up-to-date reports, we found that the ST11 KL64 CRKP subclone with high risk demonstrated significant potential for expansion and survival benefits, likely due to genetic influences. In addition, it should be noted that phage and nanoparticle treatments still pose significant risks for resistance development; hence, innovative infection prevention and control initiatives rooted in One Health principles are advocated as effective measures against K. pneumoniae transmission. In the future, further imperative research is warranted to comprehend bacterial resistance mechanisms by focusing particularly on microbiome studies’ application and implementation of the One Health strategy.