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Tigecycline is one of the last-resort treatment options for infections caused by carbapenem-resistant Klebsiella pneumoniae (KP). Unfortunately, tigecycline resistance is increasingly reported and causes an unprecedented public health crisis worldwide. Although studies on tigecycline resistance are expanding, the underlying mechanisms are not fully understood. The goal of this study is to investigate resistance-associated phenotypic changes in descendant tigecycline-resistant KP strains induced in vitro. Compared with the parental KP strains, descendant tigecycline-resistant strains grew slowly and reversed the susceptibility of carbapenems and aminoglycosides from resistance to sensitivity. The efflux pump inhibitor phenylalanyl-arginyl-β-naphthylamine (PAβN) could significantly decrease the MIC values of tigecycline in descendant strains, but the efflux pump inhibitor carbonyl cyanide-m-chlorophenylhydrazine (CCCP), verapamil, and reserpine could not. Although the descendant strains showed inconsistent (increased or decreased) biofilm formation and ethidium bromide uptake, they showed consistently decreased ethidium bromide efflux. As for the expression of efflux pumps and regulators determined by quantitative reverse transcript polymerase chain reaction (qRT-PCR), higher level of efflux pump acrAB-TolC and lower level of regulator ramA were observed in these descendant strains, while the efflux pump oqxAB and the other 6 regulators (acrR, rarA, marA, soxS, bpeT, and Rob) showed inconsistent (higher or lower) expression level. Thus, a global regulatory network driven by regulators (acrR, ramA, rarA, marA, soxS, bpeT, rob, etc.) alone or synergistically might play important roles in conferring tigecycline resistance in KP by regulation of efflux pumps (especially increasing acrAB-TolC) or other pathways.