In recent years, much attention has been paid to the exploitation of neuroprotective effects in combatting the progression and chronicity of neurodegeneration. In particular, evidence shows altered Cxs expression and functions under pathological conditions, suggesting a central role of glial GJs and HCs in the development of various neurodegenerative diseases 21, 43, 44, 45, 46. Conversely, the therapeutic potential of OECs is attracting considerable interest owing to their exceptional ability to promote functional recovery of the damaged CNS 3, 47, 48, 49, 50. However, the molecular mechanisms underlying this protective function are not yet known. The aim of this study was firstly to investigate the neuroprotective effects of OEC conditioned medium (OEC‐CM) on two different neuroblastoma cell lines (SH‐SY5Y and SK‐N‐SH) exposed to hypoxic/reoxygenation (H/R) injury. Towards this goal we explored the relationship between OEC‐CM and Cxs, HCs and GJs following H/R injury in cultures grown with and without OEC‐CM. We found that: (1) OEC‐CM offers a neuroprotective effect to the SH‐SY5Y and SK‐N‐SH cells exposed to H/R injury; (2) injured SH‐SY5Y and SK‐N‐SH cells show higher Cx43 levels compared to normoxic cultures; and (3) H/R cultures grown in the presence of GJ and/or HC chemical inhibitors, such as carbenoxolone (CBX, non‐selective GJIC inhibitor) 51, ioxynil octanoato (IO, Cx43 homotypic GJ inhibitor) 52, and Gap19 (Cx43 homotypic HC inhibitor) 53, show higher viability compared to control cultures. Our results, showing the neuroprotective effects of OEC‐CM likely afforded by inhibition of Cx43 GJ/HC signalling pathways, suggest potential new therapeutic tools against neurodegenerative diseases.