Background/Objectives: Perforated peptic ulcer (PPU) represents a surgical emergency with substantial morbidity and mortality. Despite declining overall peptic ulcer disease (PUD) incidence, contemporary population-based data comparing outcomes between perforated and non-perforated PUD remain limited, particularly during the COVID-19 pandemic. This study aimed to characterize the clinical and economic burden of PPU and identify independent predictors of adverse outcomes. Methods: We conducted a retrospective cohort study using the National Inpatient Sample (2016–2021), identifying 2,561,379 weighted hospitalizations for PUD. Hospitalizations were stratified by the presence (n = 207,970, 8.1%) or absence (n = 2,353,409, 91.9%) of perforation. The primary outcome was in-hospital mortality; secondary outcomes included sepsis, septic shock, acute kidney injury (AKI), prolonged length of stay (≥7 days), and high healthcare costs (≥$12,000). We performed 1:1 propensity score matching and multivariable logistic regression to assess independent predictors of adverse outcomes in the PPU cohort. Results: After propensity matching, PPU demonstrated significantly higher mortality than non-perforated PUD (7.2% vs. 3.0%, p < 0.001), along with increased rates of sepsis (21.8% vs. 8.2%, p < 0.001), septic shock (12.9% vs. 3.5%, p < 0.001), and AKI (29.5% vs. 22.8%, p < 0.001). Nearly half (45.6%) of PPU admissions exceeded 7 days, and 69.2% incurred costs ≥$12,000. Among PPU hospitalizations, multivariable analysis identified age ≥ 65 years (aOR 5.79, 95% CI 4.60–7.28), liver cirrhosis (aOR 1.93, 95% CI 1.62–2.30), chronic heart failure (aOR 1.73, 95% CI 1.56–1.92), and concurrent COVID-19 infection (aOR 4.35, 95% CI 3.46–5.47) as independent predictors of mortality. Chronic kidney disease strongly predicted AKI (aOR 2.81, 95% CI 2.64–2.98). Mortality increased from 6.9% (2016) to 8.0% (2021) in PPU hospitalizations (p < 0.001 for trend), with higher rates observed during the 2020 to 2021 period that coincided with the COVID-19 pandemic. Conclusions: Perforation complicates approximately 8% of hospitalized PUD cases but accounts for disproportionate mortality, sepsis, organ failure, and healthcare costs. Older age, cirrhosis, heart failure, and chronic kidney disease identify high-risk PPU patients requiring intensive monitoring and aggressive management. These findings support risk-stratified approaches focused on timely diagnosis, source control, and sepsis management to reduce the clinical and economic burden of PPU.