Aggravation of pyrethroid resistance threatens malaria control; yet, its molecular basis remains elusive. This study used a comprehensive multi-omics framework integrating 7-year gap temporal RNA-Seq, PoolSeq Whole Genome, and functional analyses, to uncover resistance escalation mechanisms in Anopheles funestus Africa-wide. Spatiotemporal analyses (2014-2021) reveal massive overexpression of novel genes (V-ATPase, tubulin alpha-1, transposase), alongside canonical resistance genes (P450s, cuticular proteins, chemosensory). Epigenetic regulators (histone H3/4, glycine N-methyltransferase) were greatly overexpressed in highly resistant mosquitoes, suggesting resistance modulation. P450-based signatures of selective sweep were detected with a drastic change in the rp1 and the P450 CYP9K1 in Central Africa. Noticeably, genomic variations at the cytochrome P450 reductase (CPR) gene were selected including a N70I mutation in Malawi [0% (2009)-80% (2021)] and a 5.9 kb promoter duplication in Ghana. Transgenic expression in Drosophila confirmed CPR-70I enhances pyrethroid resistance when co-expressed with P450-CYP6P9a, uncovering a novel CPR-mediated mechanism in intensely resistant mosquitoes. This study highlights novel candidate genes for marker development to track the spread of intensely resistant mosquitoes across Africa.