Human immune cells use a battery of toxic chemicals to eliminate invading bacteria. One of those compounds is nitric oxide (NO) and pathogens have evolved various strategies to defend themselves against this immune effector. Enzymatic detoxification is a common approach used by many bacteria, and Escherichia coli employs several enzymes to deal with NO, such as Hmp a flavohemoprotein. In addition to nitrosative stress, nutrient deprivation has been found to play an important role in phagosomal antimicrobial activity. Interestingly, recent work in Salmonella has suggested that DksA, a transcription regulator associated with the stringent response, is a molecular node for integration of nutritional and nitrosative stress signals. Here, we found that, in E. coli, loss of DksA profoundly impairs aerobic NO detoxification, approaching the detoxification capacity of Δhmp, which exhibits little-to-no NO detoxification within aerobic conditions. Investigation of this phenotype revealed that under NO stress ΔdksA suffered from low hmp transcript levels, considerably impaired protein output from the hmp promoter, and reduced catalysis by Hmp when present. These data demonstrate that DksA is critical for NO detoxification by E. coli and that loss of this regulator leads to NO defense deficiencies that span multiple levels.