To successfully live within an animal host, microbial symbionts must evade host defences that protect against invading pathogens. Integral to this is the innate immune system, considered the “first line of defence”, that guards against both biotic and abiotic stressors. Innate immune responses must be carefully regulated so that they appropriately target a stressor while avoiding damage to the host itself. One way in which this is achieved is by the generation of reactive oxygen species (ROS), which are derivatives of molecular oxygen that function in signalling cascades to activate host immune defences. Notably, the stress of invading pathogens or non-symbiotic bacteria can lead to generation of ROS and thus to activation of host defences. Symbiotic bacteria do not trigger this ROS response, which helps them maintain their symbiotic partnership, but it is not yet known how they achieve this. Here, we explore differential mechanisms of ROS generation by two transmembrane enzymes, and ROS regulation by four families of antioxidants, in a marine sponge holobiont. We find strong evidence that transcripts of one ROS-generating enzyme (DspNOX) increase during the first hour of sponge larval settlement, while transcripts of another (Duox) decrease. Notably, this period of larval settlement coincides with a dramatic shift in host microbial community composition. We show that DspNOX and Duox co-express with multiple, but distinct innate immune processes including inflammation, cell proliferation, and apoptosis. Together, our findings lead us to hypothesise that Duox and DspNOX differentially generate ROS in response to symbionts compared to pathogens, thus facilitating symbiont survival within the host.