SummaryTerrestrial runoff can negatively impact marine ecosystems through stressors including excess nutrients, freshwater, and contaminants. Severe storms, which are increasing with global climate change, generate massive inputs of runoff over short timescales (hours to days); such runoff impacted offshore reefs in the northwest Gulf of Mexico (NW GoM) following severe storms in 2016 and 2017. Several weeks after coastal flooding from these events, NW GoM reefs experienced mortality (2016 only) and/or sub-lethal stress (both years). To assess the impact of storm-derived runoff on reef filter feeders, we characterized the microbiomes of two sponges, Agelas clathrodes and Xestospongia muta, during periods of lethal stress, sub-lethal stress, and no stress over a three-year period (2016-2018). Increased anaerobes during lethal stress indicate hypoxic conditions were associated with the 2016 mortality event. Additionally, we found evidence of wastewater contamination (based on 16S libraries and quantitative PCR) in sponges 185 km offshore following storms (2016 and 2017), but not during the non-flooding year (2018). We show that water quality changes following severe storms can impact offshore benthic organisms, highlighting the need for molecular and microbial time series from near- and offshore reef ecosystems, and for the continued mitigation of stormwater runoff and climate change impacts.Originality-Significance StatementStressors associated with terrestrial runoff have contributed to substantial population declines in nearshore marine ecosystems worldwide over the last three decades. It has been assumed that offshore marine ecosystems (>100 km from land) are largely unaffected by terrestrial runoff. Our findings, however, suggest that flooding events can significantly impact offshore marine organisms, based on the detection of shifted microbiomes and human pathogens in offshore sponges after extreme storm events across two separate years, and lack of detection in a non-flooding year.