This dataset was collected to assess the effect the orange derived polyphenol hesperetin and the pomegranate derived polyphenol ellagic acid on myoblast differentiation in the presence and absence of oxidative stress, and to explore underlying mechanisms. In this in vitro cell experiment, C2C12 myoblasts were proliferated for 24h and differentiated for 120h while exposed to different concentrations of hesperetin (5, 20, 50μM), ellagic acid (0.05, 0.1μM) or a combination (20μM hesperetin, 0.05μM, 20 ellagic acid) in the absence and presence of oxidative stress-inducing compound menadione (9μM) during 24h of proliferation and during the first 5h of differentiation. The number of proliferating cells was assessed using fluorescent labelling of incorporated 5-ethynyl-2’-deoxyuridine (EdU). Myosin heavy chain (MyHC) expression was assessed by fluorescence microscopy and muscle cell fusion index was calculated as the number of nuclei inside MyHC-positive myotubes as a percentage of the total number of nuclei. Furthermore, protein expression of phosphorylated p38 and myomixer were assessed using Western blot.