We suggest novel experimental model of nerve injury-bilaterally axotomized ganglia of the crayfish ventral nerve cord (VNC). Using proteomic antibody microarrays, we showed upregulation of apoptosis execution proteins (Bcl-10, caspases 3, 6, and 7, SMAC/DIABLO, AIF), proapoptotic signaling proteins and transcription factors (c-Myc, p38, E2F1, p53, GADD153), and multifunctional proteins capable of initiating apoptosis in specific situations (p75, NMDAR2a) in the axotomized VNC ganglia. Simultaneously, anti-apoptotic proteins (p21WAF-1, MDM2, Bcl-x, Mcl-1, MKP1, MAKAPK2, ERK5, APP, calmodulin, estrogen receptor) were overexpressed. Some proteins associated with actin cytoskeleton (α-catenin, catenin p120CTN, cofilin, p35, myosin Vα) were upregulated, whereas other actin-associated proteins (ezrin, distrophin, tropomyosin, spectrin (α + β), phosphorylated Pyk2) were downregulated. Various cytokeratins and βIV-tubulin, components of intermediate filament and microtubule cytoskeletons, were also downregulated that could be the result of tissue destruction. Downregulation of proteins involved in clathrin vesicle formation (AP2α and AP2γ, adaptin (β1 + β2), and syntaxin) indicated impairment of vesicular transport and synaptic processes. The levels of L-DOPA decarboxylase, tyrosine, and tryptophan hydroxylases that mediate synthesis of serotonin, dopamine, norepinephrine, and epinephrine decreased. Overexpression of histone deacetylases HDAC1, HDAC2, and HDAC4 contributed to suppression of transcription and protein synthesis. So, the balance of multidirectional processes aimed either at cell death, or to repair and recovery, determines the cell fate. Present data provide integral, albeit incomplete, view on the nervous tissue response to axotomy. Some of these proteins can be probably potential markers of nerve injury and targets for neuroprotective therapy.