Takotsubo syndrome (TTS) and acute myocardial infarction (AMI) occasionally occur during hospitalization for non-cardiac diseases. However, no study has compared the clinical characteristics between in-hospital TTS and AMI. Using the Diagnosis Procedure Combination database in Japan between 2010 and 2014, we retrospectively identified eligible inpatients who were admitted for non-cardiac diseases and developed TTS (n = 230) or AMI (n = 611) as an early in-hospital complication diagnosed by coronary angiography within 7 days after admission. We examined factors associated with developing in-hospital TTS or AMI using multivariable logistic regression. We also compared 30-day and overall in-hospital mortality between patients with TTS and AMI using 1:1 propensity score matching. Despite similar age (72.7 ± 12.4 vs. 72.8 ± 10.4 years), patients with TTS were more often female (63.5 vs. 32.9%) and underweight (24.8 vs. 14.1%) and were more likely to have had impaired activities of daily living (ADL) and impaired consciousness than those with AMI. Multivariable logistic regression analysis showed that female sex [adjusted odds ratio: 4.16 (95% confidence interval: 2.73–6.34)], impaired ADL [2.33 (1.18–4.60)], chronic pulmonary disease [3.33 (1.49–7.44)], and pneumonia [3.00 (1.81–4.98)] were associated with developing TTS relative to AMI, while overweight status, aortic disease, cerebrovascular disease, peripheral arterial disease, and dyslipidemia were associated with developing AMI relative to TTS. Propensity score-matched analysis (189 pairs) showed that 30-day in-hospital mortality was not significantly different between patients with TTS and AMI (15.3 vs. 19.0%, p = 0.41), but overall in-hospital mortality was significantly lower in patients with TTS than in those with AMI (19.6 vs. 29.1%, p = 0.041). This study suggests that although in-hospital TTS and in-hospital AMI are similarly likely to occur in older patients, in-hospital TTS is more likely to occur in female patients with impaired ADL and/or respiratory disease and carries a similar 30-day mortality risk but a lower overall in-hospital mortality risk compared with in-hospital AMI. Our results indicate the importance of differentiating TTS from AMI in hospital settings.