<p>Coordination between different organelles and metabolic cues is crucial for resistance to pathogen invasion. As the core of maintaining cellular metabolism and homeostasis, mitochondria and lysosomes cooperate in the immune responses and elimination of intracellular pathogens. Previous research has focused on the function of one or the other in isolation, ignoring their pervasive interplay. In this review, we discuss the intricate mechanism of mitochondria-lysosome crosstalk and point out the role of AMP-activated protein kinase (AMPK)-transcription factor EB (TFEB) axis in microbial infections. The crosstalk between mitochondria and lysosomes affects cellular key processes, such as autophagy and programmed death, which play an important role in microbial infections.</p>