Social deprivation is known to trigger a variety of behavioral and physiological modifications in animal species, but the underlying genetic and cellular mechanisms are not fully understood. As we described previously, adult female flies reared in isolation show increased frequency of aggressive behaviors than those reared in a group. Here, we report that isolated rearing also caused significantly altered nerve and muscle excitability and enhanced synaptic transmission at larval neuromuscular junctions (NMJs). We found that mutations of two genes, Hyperkinetic (Hk) and glutathione S-transferase-S1 (gsts1), alter the response to social isolation in Drosophila. Hk and gsts1 mutations increased adult female aggression and larval neuromuscular hyperexcitability, even when reared in a group. Unlike wild type, these behavioral and electrophysiological phenotypes were not further enhanced in these mutants by isolated rearing. Products of these two genes have been implicated in reactive oxygen species (ROS) metabolism. We previously reported in these mutants increased signals from an ROS probe at larval NMJs, and this study revealed distinct effects of isolation rearing on these mutants, compared to the control larvae in ROS-probe signals. Our data further demonstrated modified nerve and muscle excitability by a reducing agent, dithiothreitol. Our results suggest that altered cellular ROS regulation can exert pleiotropic effects on nerve, synapse, and muscle functions and may involve different redox mechanisms in different cell types to modify behavioral expressions. Therefore, ROS regulation may take part in the cellular responses to social isolation stress, underlying an important form of neural and behavioral plasticity.