An electro-fluidic device may include a substrate having at least one substrate fluid passageway therein, and at least one substrate electrical conductor carried by the substrate. Moreover, an external interface may be spaced from the substrate and include at least one interface electrical conductor. The electro-fluidic device may also include at least one electro-fluidic interconnect extending between the substrate and the external interface. More particularly, the at least one electro-fluidic interconnect may include an interconnect body having at least one interconnect fluid passageway extending therethrough and connected to the at least one substrate fluid passageway, and at least one interconnect electrical conductor carried by the interconnect body. The at least one interconnect electrical conductor may connect the at least one substrate electrical conductor and the at least one interface electrical connector.