The intercommunication between nerves and muscles plays an important role in the functioning of our body, and its failure leads to severe neuromuscular disorders such as spinal muscular atrophy, amyotrophic lateral sclerosis etc. Understanding the cellular and molecular mechanisms underlying nerve-muscle interactions and mediating their mutual influence is an integral part of strategies aimed at the cure of neuromuscular diseases. Here, we propose a novel ex vivo experimental model for the spinal cord (SC) and skeletal muscle interactions which for the first time utilizes only fully formed postnatal tissues. The model represents an organotypic co-culture comprising a longitudinal slice of the mouse SC and an extensor digitorum longus (EDL) muscle explant placed in the “damage zone” of transversally dissected SC. Using this model we have shown that SC tissue stimulates muscle contractions, affects AChR distribution on muscle surface and directs cell migration from the muscle tissue. In turn, EDL muscles stimulate the growth of SC-derived neurites. Thus, our organotypic model allows to assess the mutual influence of neurons and muscles in an nearly natural setting which maintains the architecture and cellular composition of intact tissues. Therefore, this model may provide an effective platform for studying molecular and cellular mechanisms linked to defective neuro-muscular interactions in associated pathologies.