Inflammasome activation is essential for host immune responses during pathogenic infection and sterile signals insult, whereas excessive activation is injurious. Thus, inflammasome activation is tightly regulated at multiple layers. Ubiquitination is an important post-translational modification for orchestrating inflammatory immune responses during pathogenic infection, and a major target hijacked by pathogenic bacteria for promoting their survival and proliferation. This review summarizes recent insights into distinct mechanisms of the inflammasome activation and ubiquitination process triggered by bacterial infection. We discuss the complex regulatory of inflammasome activation mediated by ubiquitination machinery during bacterial infection, and provide therapeutic approaches for specifically targeting aberrant inflammasome activation.