Intertidal species, including many invaders, thrive in stressful and highly fluctuating environments. A prominent invasion hotspot, the Wadden Sea, witnessed the dramatic dispersal of the Pacific oyster Crassostrea gigas from aquaculture into the wild. Recent studies delving into the molecular mechanisms behind C. gigas broad stress tolerance found evidence of amplification of the genes involved in cellular stress protection and immunity. However, the potential role of host-microbiome interactions in the exceptional stress tolerance of C. gigas and the significance of the native microbiome structure for host performance in fluctuating environments remain unexplored. To understand the link between microbiome integrity and the host"s physiological performance under stress, we investigated the impact of antibiotic-induced microbiome disturbance on oysters" responses to abiotic stress including intermittent hypoxia, temperature, and salinity fluctuations. We analyzed microbiome dynamics in gills, digestive glands, and haemolymph of 300 C. gigas using high-throughput sequencing of the 16S rRNA gene with the DADA2 algorithm pipeline. Statistical analyses determined temporal shifts, alpha and beta diversity, and taxonomic composition of oyster microbiome under different conditions. We found pronounced within-individual heterogeneity in microbial composition across tissues, with Proteobacteria, Bacteroidota, Spirochaetia, and Firmicutes consistently dominating. Antibiotic treatment induced significant shifts in alpha diversity, indicating temporal changes in depletion effects. Moreover, the microbiome responded deferentially to stressors when combined with antibiotic disruption, with outcomes varying across tissues. We observed marked taxonomic alterations in antibiotic-depleted oysters, rendering the native microbiome more susceptible to a shift toward a community dominated by opportunistic pathogens, thereby increasing disease risk. These observed shifts in microbial composition and diversity offer valuable insights into the resilience of oyster-associated bacteria and their potential implications for host health and survival in the face of environmental challenges.