Animal responses to bacteria, viruses and other microorganisms are important to understand how host-microbe interactions lead to divergent molecular responses by the host and the assembly of the holobiont. The immune system of the animal and the resident microbial community are critical factors in the response, or lack thereof, by a host to a newly encountered microbe. Here, we describe the transcriptional response of the model cnidarian Nematostella vectensis when exposed to three Live Cell (LC) isolates (Bacillus velezensis, Pseudoalteromonas spiralis, and Vibrio diabolicus) or their Cell Free Supernatants (CFS) with and without the native microbiome. Gene expression revealed large variation in the overall response ranging from nearly 1000 differentially expressed genes (DEGs) for axenic anemones exposed to B. velezensis to 49 DEGs in xenic individual inoculated with V. diabolicus. The anemone’s response similarly varied widely if the exposure was to the live bacteria or the secreted products, especially with B. velezensis. Genes associated with the RIG-I-like immune pathway showed large differences in expression whereas the transcriptional variation for NF-kB and toll-like receptor were not significantly different. The response to each gram-negative bacteria differed from a purified bacterial ligand lipopolysaccharides (LPS). Together, these results support the hypothesis that N. vectensis mounts unique transcriptional responses to individual bacterial species and their products, which is dependent on the presence of the native microbiome. The complexity of this molecular response further highlights the dynamic interplay between cnidarians and microbes in the assembly and maintenance of the holobiont.