Spontaneous functional mammalian axonal regeneration following injury fails. High density and fast axon regeneration across distances are needed for efficient repair in humans. These are likely influenced by complex neuronal intrinsic and extrinsic metabolic and signalling mechanisms. Environmental factors such as exercise and diet have been shown to affect metabolism and signalling promoting health and repair processes in several diseases. Intermittent fasting (IF) has been shown to increase synaptic plasticity and neurogenesis that partially share molecular mechanisms with axonal regeneration. Recent publications showed that IF was followed by enhanced functional recovery following spinal cord injury. We hypothesized that IF would promote axonal regeneration after injury by a combinatorial effect of systemic and cell intrinsic mechanisms influencing neuronal metabolism and regenerative signalling pathways. Hence, we studied axonal regeneration after sciatic nerve injury in fasting (IF) versus non-fasting animals to discover that IF significantly promotes axonal regeneration. We next found IF-dependent upregulation of gut bacteria-derived indole metabolites and identified indole-3-propionic acid (IPA) as a key factor in IF dependent axonal regeneration. IPA treatment in ad libitum-fed mice increased axonal regeneration after injury. Further, RNA sequencing transcriptomic analysis from dorsal root ganglia neurons suggests that neutrophils and interferon gamma play an important role in IPA-dependent axonal regeneration. These studies offer both a novel mechanism and they have the potential to provide a novel translational approach for nerve repair and functional recovery after injury.