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An inhibitory extracellular milieu and neuron-intrinsic processes prevent axons from regenerating in the adult central nervous system (CNS). Here we show how the two aspects are interwoven. Genetic loss-of-function experiments determine that the small GTPase RhoA relays extracellular inhibitory signals to the cytoskeleton by adapting mechanisms set in place during neuronal polarization. In response to extracellular inhibitors, neuronal RhoA restricts axon regeneration by activating myosin II to compact actin and, thereby, restrain microtubule protrusion. However, astrocytic RhoA restricts injury-induced astrogliosis through myosin II independent of microtubules by activating Yes-activated protein (YAP) signaling. Cell-type-specific deletion in spinal-cord-injured mice shows that neuronal RhoA activation prevents axon regeneration, whereas astrocytic RhoA is beneficial for regenerating axons. These data demonstrate how extracellular inhibitors regulate axon regeneration, shed light on the capacity of reactive astrocytes to be growth inhibitory after CNS injury, and reveal cell-specific RhoA targeting as a promising therapeutic avenue. [Display omitted] • RhoA has opposing roles in neurons and astrocytes during CNS regeneration • Neuronal RhoA prevents axon regeneration by mechanisms that recapitulate polarization • Astrocytic RhoA drives actin compaction to activate YAP, restricting astrogliosis • Axon regeneration is only stimulated when RhoA is ablated specifically in neurons Stern et al. reveal cell type-specific roles of RhoA that affect axon regeneration in opposite ways. By acting on the cytoskeleton, neuronal RhoA restrains axon regrowth, but astrocytic RhoA attenuates inhibitory astrocyte reactivity. Therefore, only neuron-specific RhoA ablation stimulates regeneration. [ABSTRACT FROM AUTHOR]