The increasing resistance to cephalosporins inSalmonellaposes a serious threat to public health. In our previous study, theblaCTX-M-101gene, a newblaCTX-Mvariant, was first reported inSalmonella entericaserovar Enteritidis (S.Enteritidis). Here, we further analyzed the genome characterization, transferability, and resistance mechanism of oneS.Enteritidis isolate (SJTUF14523) carryingblaCTX-M-101from an outpatient in 2016 in Xinjiang, China. This strain was a multidrug resistance (MDR) isolate and exhibited resistance to ceftazidime (MIC = 64 μg/mL), cefotaxime (MIC = 256 μg/mL), and cefepime (MIC = 16 μg/mL). Phylogenetic analysis revealed that SJTUF14523 had a close relationship to anotherS.Enteritidis isolate from the United States. In the presence of plasmid p14523A, there were 8- and 2133-fold increases in the MICs of cephalosporins inEscherichia coliC600 in the conjugation. Gene cloning results indicated thatblaCTX-M-101was the decisive mechanism leading to ceftazidime and cefotaxime resistance that could make the MICs break through the resistance breakpoint. Plasmid sequencing revealed that theblaCTX-M-101gene was located on an IncI1-Iα transferable plasmid (p14523A) that was 85,862 bp in length. Sequence comparison showed that p14523A was a novel hybrid plasmid that might have resulted from the interaction between a homologous region. Furthermore, we found a composite transposon unit composed of ISEcp1,blaCTX-M-101, andorf477 in p14523A. ISEcp1-mediated transposition was likely to play a key role in the horizontal transfer ofblaCTX-M-101among plasmids inS.Enteritidis. Collectively, these findings underline further challenges in the prevention and control of antibiotic resistance posed by new CTX-M-101-like variants inSalmonella.