Stony coral tissue loss disease (SCTLD) remains an unprecedented disease outbreak due to its high mortality rate and rapid spread throughout Florida’s Coral Reef and wider Caribbean. A collaborative effort is underway to evaluate disease intervention strategies that mitigate the spread of SCTLD across coral colonies and reefs. We conducted an in-situ experiment in Southeast Florida to assess molecular responses among SCTLD-affected Montastraea cavernosa pre- and post-application of the most widely-used intervention method, CoreRx Base 2B with amoxicillin. Through Tag-Seq gene expression profiling of apparently healthy, diseased, and treated corals, we identified modulation of metabolomic and immune pathways following antibiotic treatment. In a complementary ex-situ disease challenge experiment, we exposed nursery-cultured M. cavernosa and Orbicella faveolata fragments to SCTLD-affected donor corals to compare transcriptomic profiles among clonal individuals from unexposed controls, those exposed and displaying disease signs, and corals exposed and not displaying disease signs. Suppression of metabolic functional groups and activation of stress gene pathways as a result of SCTLD exposure were apparent in both species. Amoxicillin treatment led to a ‘reversal’ of the majority of gene pathways implicated in disease response, suggesting potential recovery of corals following antibiotic application. In addition to increasing our understanding of molecular responses to SCTLD, we provide resource managers with transcriptomic evidence that disease interventions with antibiotics appear to be successful and may help to modulate coral immune responses to SCTLD. These results contribute to feasibility assessments of intervention efforts following disease outbreaks and improved predictions of coral reef health in Southeast Florida.