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The emergence of extended-spectrum β-lactamase-producing <i>Salmonella enterica</i> serovar Enteritidis (ESBL-SE) in humans and foods has gained global attention. In particular, CTX-M-type ESBL-SE are increasingly being detected from various sample types. The aim of this study was to comprehensively analyze the epidemiology and characteristics of <i>bla</i>_CTX-M-55-carrying ESBL-SE isolates of clinical origin in Shanghai, China. A total of 292 <i>S.</i> Enteritidis isolates were recovered from the feces and blood of outpatients and inpatients between 2006 and 2014. Overall, there was a high frequency of cefotaxime-resistant isolates (97.3%), which was significantly higher (<i>p</i> < 0.01) than that of isolates resistant to the other tested antibiotics. All <i>S.</i> Enteritidis isolates exhibited resistance to ≥1 antibiotic, and 98.0% were multidrug resistant. A total of 233 isolates were identified as ESBL-SE, 166 of which were CTX-M type. Six subtypes of CTX-M-encoding genes were detected, among which <i>bla</i>_CTX-M-55 (91.6%, 152/166) was the most prevalent genotype. There was high genetic similarity among <i>bla</i>_CTX-M-55-positive ESBL-SE. The <i>bla</i>_CTX-M-55 gene in the ESBL-SE donor strains could be easily transferred into <i>Enterobacteriaceae</i> recipient strains. This study highlights that CTX-M-55 should be considered an important surveillance target in Shanghai, China. Cephalosporins, especially cefotaxime, must be used with caution in empirical treatment for <i>Salmonella</i> infections.