In this work, we describe a systematic comparative genomic analysis of promiscuous domains in genomes of Bacteria and Archaea. A quantitative measure of domain promiscuity, the weighted domain architecture score (WDAS), was used and applied to 1317 domains in 1320 genomes of Bacteria and Archaea. A functional analysis associated with the WDAS per genome showed that 18 of 50 functional categories were identified as significantly enriched in the promiscuous domains; in particular, small-molecule binding domains, transferases domains, DNA binding domains (transcription factors), and signal transduction domains were identified as promiscuous. In contrast, non-promiscuous domains were identified as associated with 6 of 50 functional categories, and the category Function unknown was enriched. In addition, the WDASs of 52 domains correlated with genome size, i.e., WDAS values decreased as the genome size increased, suggesting that the number of combinations at larger domains increases, including domains in the superfamilies Winged helix-turn-helix and P-loop-containing nucleoside triphosphate hydrolases. Finally, based on classification of the domains according to their ancestry, we determined that the set of 52 promiscuous domains are also ancient and abundant among all the genomes, in contrast to the non-promiscuous domains. In summary, we consider that the association between these two classes of protein domains (promiscuous and non-promiscuous) provides bacterial and archaeal cells with the ability to respond to diverse environmental challenges.