The impact of global climate change has highlighted the need for a better understanding of how plants respond to multiple simultaneous or sequential stresses, not only to gain fundamental knowledge of how plants integrate signals and mount a coordinated response to stresses but also for applications to improve crop resilience to environmental stresses. In recent years, there has been a stronger emphasis on understanding how plants integrate stresses and the molecular mechanisms underlying the crosstalk between the signaling pathways and transcriptional programs that underpin plant responses to multiple stresses. The combination of flooding (or resulting hypoxic stress) with pathogen infection is particularly relevant due to the frequent co-occurrence of both stresses in nature. This review focuses on (i) experimental approaches and challenges associated with the study of combined and sequential flooding/hypoxia and pathogen infection, (ii) how flooding (or resulting hypoxic stress) influences plant immunity and defense responses to pathogens, and (iii) how flooding contributes to shaping the soil microbiome and is linked to plants’ ability to fight pathogen infection.