The emergence of KPC variants associated with ceftazidime/avibactam resistance may also compromise the activity of other recently developed β-lactams, including cefiderocol and cefepime/taniborbactam. Xeruborbactam is a boronic acid β-lactamase inhibitor with potent activity against serine- and metallo-β-lactamases and is currently under clinical development in combination with cefiderocol. We evaluated the in vitro activity of cefiderocol/xeruborbactam against a panel of clinical Klebsiella pneumoniae isolates and isogenic Escherichia coli transformants (including both wild-type and porin-deficient backgrounds) producing KPC variants. Xeruborbactam and taniborbactam activities were compared using ceftazidime, cefepime, and cefiderocol as reporter substrates. Inhibitory activity was analyzed by determining the IC₅₀ values for both inhibitors against KPC variants. Most clinical isolates producing KPC variants showed increased MIC values and substantial cross-resistance to ceftazidime/avibactam, cefiderocol, and cefepime/taniborbactam. Cefiderocol/xeruborbactam retained potent activity against all clinical isolates, regardless of the KPC variant produced or the outer membrane permeability status. These findings were confirmed in wild-type and porin-deficient isogenic E. coli models, in which the combination of KPC variants and porin loss synergistically increased resistance to multiple β-lactams, while cefiderocol/xeruborbactam consistently restored susceptibility to wild-type levels. Comparative MIC analyses showed that xeruborbactam enhanced the activity of all β-lactam partners to a greater extent than taniborbactam. IC₅₀ determinations revealed a 17-fold to 73-fold greater inhibitory potency of xeruborbactam, which was maintained across structurally diverse KPC variants. Overall, cefiderocol/xeruborbactam exhibited potent activity against KPC-producing Enterobacterales, including isolates producing KPC variants associated with reduced susceptibility or resistance to ceftazidime/avibactam, cefiderocol, and cefepime/taniborbactam.