Utilizing enzyme therapy to repair the spinal cord injury has originated from the fact that various types of chondroitin sulfate proteoglycans (CSPGs) are secreted in the glial scar by activated astrocytes at the site of damage following spinal cord injury (SCI). These compounds act as a physical barrier against axonal regrowth, sprouting, and synaptic reorganization. On the other hand, Chondroitinase ABC I (cABC I) from Proteus Vulgaris with the ability to degrade these molecular inhibitors has been introduced as a potential therapeutic agent to help nerve regeneration. It has three specific domains, including the N- and C-terminals, as well as the central catalytic domain. Its activity to degrade CSPGs depends on the formation of the open and closed conformations due to the presence of substrate molecules. Environmental conditions of the human body in the SCI region affect the half-life and catalytic efficiency of the recombinant cABC I, as it has a microbial source. Accordingly, it seems that high concentration of the enzyme should be used to observe a marked activity of the protein. However, increasing the concentration of the enzyme leads to the occurrence of molecular aggregation at 37 °C. To reach a remarkable result, repeated enzyme injections to the patients under treatment have also been proposed. However, increasing the number of administrations in a limited time period leads to an immunogenicity response accompanied by various side effects. To overcome these challenges and to gain significant functional outcomes, a combination of protein engineering and drug delivery strategies should be developed to prepare and utilize the enzyme in a defined therapeutic window. Considering the various pathological consequences of SCI, combinatorial approaches and other medical interventions and rehabilitation are being developed for locomotor recovery.