We investigated the incidence of post-intubation hypotension (PIH) in hemodynamically stable patients with STEMI requiring rapid sequences intubation (RSI) and medicated with ketamine or midazolam as induction agent. STEMI patients admitted between 1st January 2009 and 1st January 2017 who did not receive any type of inotropic support before the endotracheal intubation (ETI) was reviewed. PIH was defined as a reduction greater than 20% or a drop of systolic blood pressure (SBP) below 90 mmHg within 10 min from the administration of the induction agent [ketamine (1 mg/kg) or midazolam (0.3 mg/kg)]. Over the study period, 136 patients (66 male and 70 females, mean age 72.25 ± 7.33 years) met the inclusion criteria. Patients treated with midazolam and ketamine were 63 and 73, respectively. PIH was observed in 38 (27.9%) patients after 10 min from ETI. Midazolam patients had a significant lower SBP at both 5 and 10 min after induction (97.75 ± 8.06 vs 100.81 ± 8.08, p = 0.029 and 92.83 ± 7.53 vs 101.58 ± 7.29, p < 0.0001, respectively) (ANOVA p < 0.0001). Age (OR 1.91, 95% CI 1.87–1.97, p = 0.001), history of arterial hypertension (OR 2.27, 95% CI 2.21–2.35, p = 0.0001), multivessel coronary artery disease (OR 2.66, 95% CI 2.58–2.71, p = 0.001), SI ≥0.9 (OR 2.41, 95% CI 2.36–2.48, p < 0.0001) and anterior STEMI (OR 2.51, 95% CI 2.48–2.57, p = 0.0001) resulted independent predictors of PIH in STEMI patients treated with midazolam, as induction agent, before ETI. Midazolam was more likely than ketamine to cause significant PIH when used as an induction agent for RSI in hemodynamically stable patients with STEMI.