To investigate the possible interplay between OEC‐CM and Cx43 in protection after H/R injury, the effects of Cx43 chemical inhibition has been assessed. When H/R stress is induced in SH‐SY5Y cells, both Cx43‐GJ and Cx43‐HC chemical inhibition significantly increased the cell viability over time compared to control cultures. The functional modulation of Cx43 provides additional support on its involvement in OEC‐CM mediated neuroprotection, likely exerted through the prevention of the spread of injury signals. One appealing hypothesis is that OEC‐CM works by influencing Cx43 expression in the SH‐SY5Y cells via paracrine factors likely involved in the physiological role of OECs within the CNS.