Background <p><i>Edwardsiella tarda</i> (<i>E. tarda</i>) causes highly mortality, which is rare in septic patients. We herein reported a case of septic shock caused by drug-resistant <i>E. tarda</i>.</p> Case presentation <p>We herein describe a 32-year-old female with septic shock who had the medical history of abortion 1 month ago and “systemic lupus erythematosus and rheumatoid arthritis” presented abdominal pain, diarrhea, and dyspnea as the primary symptoms and rapidly deteriorated to MODS following breakfast (undercooked fish porridge) in the ICU. Sepsis surviving bundle was initiated by collecting pathogen culture (sputum, urine and blood samples), empirically broad-spectrum antibiotics administration (Meropenem), along with fluid resuscitation, vasopressor use. <i>E. tarda</i> was confirmed both in blood culture and mNGS (metagenomics next generation sequencing). Thus, the antibiotics were switched to piperacillin-tazobactam according to the susceptibility test that was susceptible to piperacillin-tazobactam and resistant to ampicillin, quinolones and gentamicin. The patient finally recovered and discharged after 18 days of ICU treatment.</p> Conclusions <p>Empiric antibiotics should be selected with piperacillin-tazobactam and amikacin, and avoid ampicillin, quinolones and gentamicin for suspecting <i>E. tarda</i> infection in southern China. Bacteremia complicated with septic shock caused by <i>E. tarda</i> requires intensive care to improve survival rates.</p>