mosquitoes, such as dengue, Zika, and chikungunya, have expanding ranges and seem unabated by current vector control programs. Effective control of these pathogens likely requires integrated approaches. We evaluated dengue management options in an endemic setting that combine novel vector control and vaccination using an agent-based model for Yucatán, Mexico, fit to 37 y of data. Our intervention models are informed by targeted indoor residual spraying (TIRS) experiments; trial outcomes and World Health Organization (WHO) testing guidance for the only licensed dengue vaccine, CYD-TDV; and preliminary results for in-development vaccines. We evaluated several implementation options, including varying coverage levels; staggered introductions; and a one-time, large-scale vaccination campaign. We found that CYD-TDV and TIRS interfere: while the combination outperforms either alone, performance is lower than estimated from their separate benefits. The conventional model hypothesized for in-development vaccines, however, performs synergistically with TIRS, amplifying effectiveness well beyond their independent impacts. If the preliminary performance by either of the in-development vaccines is upheld, a one-time, large-scale campaign followed by routine vaccination alongside aggressive new vector control could enable short-term elimination, with nearly all cases avoided for a decade despite continuous dengue reintroductions. If elimination is impracticable due to resource limitations, less ambitious implementations of this combination still produce amplified, longer-lasting effectiveness over single-approach interventions.