Antioxidants are substances that protect cells from the damaging effects of oxygen radicals, which are chemicals that play a part in some diseases such as cancer and others. Antioxidants are expected to be promising drugs in the management of these diseases by removing oxidative stress. Most of the modeling approaches involved in designing new antioxidants is based on Quantitative Structure-Activity Relationship (QSAR). A number of QSAR studies have been conducted to elucidate the structural requirements of antioxidants for their activities in order to predict the potency of these compounds with regard to the targeted activity and to direct the synthesis of more potent analogues. The main focus of this chapter is on the QSAR modeling of antioxidant compounds. The authors provide different QSAR studies of antioxidant compounds and try to compare between them in terms of the best models obtained and their use in designing potential new drugs.