Hybrid breakdown, or outbreeding depression, is the loss of fitness observed in crosses between genetically divergent populations. The role of maternally inherited mitochondrial genomes in hybrid breakdown has not been widely examined. Using laboratory crosses of the marine copepod Tigriopus californicus, we report that the low fitness of F(3) hybrids is completely restored in the offspring of maternal backcrosses, where parental mitochondrial and nuclear genomic combinations are reassembled. Paternal backcrosses, which result in mismatched mitochondrial and nuclear genomes, fail to restore hybrid fitness. These results suggest that fitness loss in T. californicus hybrids is completely attributable to nuclear-mitochondrial genomic interactions. Analyses of ATP synthetic capacity in isolated mitochondria from hybrid and backcross animals found that reduced ATP synthesis in hybrids was also largely restored in backcrosses, again with maternal backcrosses outperforming paternal backcrosses. The strong fitness consequences of nuclear-mitochondrial interactions have important, and often overlooked, implications for evolutionary and conservation biology.