Free radicals and oxidants can cause oxidative damage to physiologically important biomolecules that subsequently leads to the development of a wide range of chronic and degenerative diseases such as aging, cancer, cardiovascular and neurodegenerative diseases. Antioxidants have been shown to be instrumental in counteracting the deleterious effects of these reactive oxygen species. Herein, a series of 20 pyrazolopyridine derivatives with antioxidant activity were utilized for constructing a quantitative structure–activity relationship model as to unravel the origins of the antioxidant activity. Quantum chemical and molecular descriptors were used to quantitate the physicochemical properties of investigated compounds. Significant descriptors as identified by stepwise regression analysis consisted of Mor11m, Mor25v, JGI5, H8p, GATS5p, and GVWAI-50. Statistical parameters suggested that the constructed quantitative structure–activity relationship models were robust with $Q^2$ = 0.9370 and root mean square error = 4.7414 as evaluated via leave-one-out cross-validation. The mechanistic basis of the antioxidant activity as deduced from significant descriptors was rationalized. Particularly, compounds with the highest antioxidant activity required compounds to have the highest mean topological charge index of order 5 (JGI5) and Geary autocorrelation–lag 5/weighted by atomic polarizabilities (GATS5p) but necessitated low 3D-MoRSE-signal 25/ weighted by atomic van der Waals volumes (Mor25v). Such properties are well corroborated by the 3-aminopyrazole pharmacophore from investigated compounds. Molecular insights unraveled herein is anticipated to be useful as guidelines for further rational design of novel pyrazole analogs with potent antioxidant activity.