Reactive oxygen species/nitrogen species (ROS/RNS) are major causative agents of oxidative stress related diseases such as neurodegenerative, cancer, cardiovascular, and inflammation via intracellular signal transduction pathways. Synthetic modification of antioxidants and development of hybrid compounds by conjugation or integration of two or more moiety opened a new era in development of antioxidant based therapeutics. In this review, our attention is focused on structural, chemical and biochemical feature of free radicals, description of mechanistic modulation in signaling pathways by antioxidants and establishment of relationship between structural and biological accepts of antioxidant hybrid systems (1,2-dithiolone, α,β-unsaturated carbonyl, cinnamate based hybrids and miscellaneous hybrids).