Salinity change in coastal zone is a common phenomena which can put several coastal soft bottom organisms under stressed condition. These stress could be mediated through their mitochondrial functions. In this data set, we present the effect of acclimation to three different salinity regime (normal: 15 psu, low: 5 psu and fluctuating: daily salinity cycle between 5 and 15 psu) on the mitochondrial performance (MO2) of soft shell clam, Mya arenaria. Clams were acclimated to normal, low and fluctuating salinity; the mitochondrial respiration of these clams was then measured under two different osmolarity (450 and 150 mOsm, representing 15 and 5 psu, respectively). MO2 was measured sequentially, starting with the addition of pyruvate and malate, succinate, ADP, oligomycin, CCCP, rotenon, antimycin A, TMPD and ascorbate, and finally KCN.