Background and objectives: Primary percutaneous coronary intervention (PCI)-related outcomes in acute myocardial infarction (AMI) have improved over time, but there are limited data on the length of stay (LOS) in relation to in-hospital mortality. Materials and Methods: A retrospective cohort of adult AMI admissions was identified from the National Inpatient Sample (2000–2017) and stratified into short (≤3 days) and long (>3 days) LOS. Outcomes of interest included temporal trends in LOS and associated in-hospital mortality, further sub-stratified based on demographics and comorbidities. Results: A total 11,622,528 admissions with AMI were identified, with a median LOS of 3 (interquartile range [IQR] 2–6) days with 49.9% short and 47.3% long LOS, respectively. In 2017, compared to 2000, temporal trends in LOS declined in all AMI, with marginal increases in LOS >3 days and decreases for ≤3 days (median 2 [IQR 1–3]) vs. long LOS (median 6 [IQR 5–9]). Patients with long LOS had lower rates of coronary angiography and PCI, but higher rates of non-cardiac organ support (respiratory and renal) and use of coronary artery bypass grafting. Unadjusted in-hospital mortality declined over time. Short LOS had comparable mortality to long LOS (51.3% vs. 48.6%) (p = 0.13); however, adjusted in-hospital mortality was higher in LOS >3 days when compared to LOS ≤ 3 days (adjusted OR 3.00, 95% CI 2.98–3.02, p < 0.001), with higher hospitalization (p < 0.001) when compared to long LOS. Conclusions: Median LOS in AMI, particularly in STEMI, has declined over the last two decades with a consistent trend in subgroup analysis. Longer LOS is associated with higher in-hospital mortality, higher hospitalization costs, and less frequent discharges to home compared to those with shorter LOS.