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The aim of this study was to compare the reference broth microdilution (BMD) method with the Disk Diffusion (DD) test and strip test against a collection of 75 well-characterized <i>Klebsiella pneumoniae</i> carbapenemase (KPC)-producing <i>Klebsiella pneumoniae</i> (KPC-Kp) clinical strains to assess cefiderocol (CFD) antimicrobial activity. Whole-genome sequencing was performed on KPC-Kp strains by Illumina iSeq100 platform. The Categorical Agreement (CA) between the BMD method and DD test was 92% (69/75) with a Major Error (ME) of 16.7% (6/36). Additionally, the CA between the BMD method and test strip was 90.7% (68/75) with a Very Major Error (VME) of 17.9% (7/39) and 82.7% (62/75) between the strip test and DD with a ME of 30.2%. KPC-Kp strains showing resistance to CFD were 27 out of 75 (36%) by three methods. Specifically, 51.9% (14/27) of KPC-Kp resistant to CFD harbored <i>bla</i>_KPC-3, while 48.1% (13/27) harbored mutated <i>bla</i>_KPC-3. Moreover, KPC-Kp strains carrying a mutated <i>bla</i>_KPC-3 gene exhibited high MIC values (<i>p</i> value < 0.001) compared to wild-type <i>bla</i>_KPC-3. In conclusion, the DD test resulted as a valid alternative to the BMD method to determine the in vitro susceptibility to CFD, while the strip test exhibited major limitations.