The class of pyrazolo [1, 5 − a] pyridine–1,3,4-oxadiazole chalcones features a fused heterocycle aromatic ring system, an oxadiazole moiety as a linker, and an electronically tailorable α, β-unsaturated carbonyl group. In this study, we sought to examine whether the anticancer effectiveness of 11a–j compounds depends on aryl substituents’ electronics instead of merely on their lowest IC50 order. The cytotoxicity matrix for MCF-7, A549, Colo-205, and A2780 was first converted into pIC50 parameters. Then, aryl patterns were coded in terms of the summed Hammett constant (Σσ). Relative potency scores were estimated against etoposide and related to mechanism-discriminating laboratory experiments. For the whole set of ten compounds, a very strong positive correlation of Σσ with the mean value of pIC50 was detected both through Pearson’s r (r = 0.873; p = 9.84 × 10−4) and Spearman’s ρ (ρ = 0.796; p = 5.84 × 10−3). One-electronic descriptor accounted for 76.2% of variance in pIC50 scores within compounds. A similar trend persisted for each cell line individually: MCF-7, A549, Colo-205, A2780. Compound 11j appeared the most effective in particular, among A549. Yet, its high potency comes along with dinitro substitution that requires further validation of selectivity, redox, and target-binding.