A one-step synthesis of diversely substituted pyrazolo[1,5-a]pyrimidines from saturated ketones and 3-aminopyrazoles is presented. This transformation involves the in situ formation of α,β-unsaturated ketones via a radical process, followed by [3+3] annulation with 3-aminopyrazoles in one pot. Mechanistic studies have shown that the dual C(sp3)–H bond functionalization of inactive ketones is required for the formation of the title compounds. Notably, this dehydrogenative coupling process provides access to a host of functionalized pyrazolo[1,5-a]pyrimidines with antitumor potential from commercially available substrates.