We sought to determine if the innate immune response is under circadian regulation and whether this impacts overall health status. To this end, we used infection of Drosophila with the human opportunistic pathogenic bacteria Pseudomonas aeruginosa as our model system . We show that the survival rates of wild-type flies vary as a function of when, during the day, they are infected, peaking in the middle of the night. Although this rhythm is abolished in clock mutant flies, those with an inactive period gene are highly susceptible to infection, whereas mutants with impairment in other core clock genes exhibit enhanced survival. After an initial phase of strong suppression, the kinetics of bacterial growth correlate highly with time of day and clock mutant effects on survival. Expression profiling revealed that nighttime infection leads to a clock-regulated transient burst in the expression of a limited number of innate immunity genes. Circadian modulation of survival also was observed with another pathogen, Staphylococcus aureus. Our findings suggest that medical intervention strategies incorporating chronobiological considerations could enhance the innate immune response, boosting the efficacy of combating pathogenic infections.