Ferrochelatase-1 as a terminal enzyme of heme biosynthesis regulates many essential metabolic and physiological processes. Whether FC1 is involved in plant response to salt stress has not been described. This study shows that Arabidopsis overexpressing AtFC1 displays resistance to high salinity, whereas a T-DNA insertion knock-down mutant fc1 was more sensitive to salt stress than wild-type plants. AtFC1 conferred plant salt resistance by reducing Na+ concentration, enhancing K+ accumulation and preventing lysis of the cell membrane. Such observations were associated with the upregulation of SOS1, which encodes a plasma membrane Na+/H+ antiporter. AtFC1 overexpression led to a reduced expression of several well known salt stress-responsive genes such as NHX1 and AVP1, suggesting that AtFC1-regulated low concentration of Na+ in plants might not be through the mechanism for Na+ sequestration. To investigate the mechanism leading to the role of AtFC1 in mediating salt stress response in plants, a transcriptome of fc1 mutant plants under salt stress was profiled. Our data show that mutation of AtFC1 led to 490 specific genes up-regulated and 380 specific genes down-regulated in fc1 mutants under salt stress. Some of the genes are involved in salt-induced oxidative stress response, monovalent cation-proton (Na+/H+) exchange, and Na+ detoxification.