Summary Dehong humped cattle (DHH) is an indigenous zebu breed from southwestern China that possesses characteristics of heat tolerance and strong disease resistance and adapts well to the local tropical and subtropical climatic conditions. However, information on selection signatures of DHH is scarce. Herein, we compared the genomes of DHH and each of Diqing and Zhaotong cattle breeds using the population differentiation index (FST), cross‐population extended haplotype homozygosity (XP‐EHH) and cross‐population composite likelihood ratio (XP‐CLR) methods to explore the genomic signatures of heat tolerance and disease resistance in DHH. Several pathways and genes carried selection signatures, including thermal sweating (calcium signaling pathway), heat shock (HSF1) and oxidative stress response (PLCB1, PLCB4), coat color (RAB31), feed intake (ATP8A1, SHC3) and reproduction (TP63, MAP3K13, PTPN4, PPP3CC, ADAMTSL1, SS18L1, OSBPL2, TOX, RREB1, GRK2). These identified pathways and genes may contribute to heat tolerance in DHH. Simultaneously, we also identified LIPH, TP63 and CBFA2T3 genes under positive selection that were associated with immunity.