Background: Takotsubo Syndrome (TTS) is a transient left ventricular systolic dysfunction typically characterized by anteroseptal-apical dyskinetic ballooning of the left ventricle with a hyperkinetic base, without significant obstructive coronary artery disease. The interplay between systemic inflammation and hemodynamic stress in sepsis exacerbates susceptibility to TTS. We aim to investigate the characteristics and factors associated with TTS in critically ill patients with sepsis admitted to the intensive care unit. Methods: A retrospective cohort study was conducted on 361 patients admitted to the medical ICU at a tertiary care hospital in New York City. All patients underwent transthoracic echocardiography (TTE) within 72 h of sepsis diagnosis. Patients were divided into TTS and non-TTS groups. Clinical data, comorbidities, and hemodynamic parameters were extracted from electronic medical records and analysed using multivariate logistic regression to determine independent predictors of TTS. Results: Among 361 patients, 24 (6.65%) were diagnosed with TTS. Female sex (OR 3.145, 95% CI 1.099–9.003, p = 0.033) and higher shock index (OR 4.454, 95% CI 1.426–13.910, p = 0.010) were significant predictors of TTS. Individuals with ≥ 25 kg/m² had a lower odds of developing TTS as compared to their obese counterparts (OR 0.889, 95% CI 0.815–0.969, p = 0.007). Conclusions: The findings highlight that Female sex, higher shock index and a BMI < 25 kg/m² emerge as possible predictors for development of TTS in patients with sepsis. Further research is needed to unravel the mechanisms behind the “obesity paradox” in TTS and optimize clinical strategies for high-risk patients.