Background: Syphilis, a major sexually transmitted infection, may contribute to cardi-ovascular complications, impacting hospital outcomes and costs. This study evaluates the association between syphilis burden and hospitalization outcomes (cost, length of stay, and aneurysm mortality) across Brazilian regions from 2010 to 2024. Methods: Using Brazil’s national healthcare database (n = 405 state-year observations), we classified states by syphilis burden (high, low, intermediate) based on hospitalization rates. Outcomes included average hospitalization cost (R17.7M (high burden), R$1.9M (low), and R$12.0M (intermediate). Regional analyses revealed significant interactions in Nordeste and Norte for length of stay (p = 0.013–0.033). Sensitivity analyses confirmed robustness (Adjusted R² = 0.049–0.273). Conclusion: High syphilis burden is linked to reduced hospital stays, potentially re-flecting fewer complex cases, with substantial economic costs. Regional disparities highlight the need for targeted STI prevention. These findings inform health policy to mitigate syphilis-related hospital burdens in Brazil.