Polyunsaturated fatty acids (PUFAs) have diverse health-promoting effects, such as potentially protecting in immune, nervous, and cardiovascular systems by targeting a variety of sites, including most ion channels. Voltage-gated potassium channels of the K_V7 family and large-conductance Ca²⁺- and voltage-activated K⁺ (BK_Ca) channels are expressed in many tissues, therefore, their physiological importance is evident from the various disorders linked to dysfunctional K_V7 channels and BK_Ca channels. Thus, it is extremely important to learn how potassium channels are regulated by PUFAs. The aim of this review is to provide an overview of the effects of PUFAs on K_V7 channels and BK_Ca channels functions, as well as the mechanisms underlying these effects. In summarizing reported effects of PUFAs on K_V7 and BK_Ca channels mediated currents, we generally conclude that PUFAs increase the current amplitude, meanwhile, differential molecular and biophysical mechanisms are associated with the current increase. In K_V7 channels the currents increasement are associated with a shift in the voltage dependence of channel opening and increased maximum conductance in K_V7 channels, while in BK_Ca channels, they are associated with destabilization the pore domain closed conformation. Furthermore, PUFA effects are influenced by auxiliary subunits of K_V7 and BK_Ca channels, associate with channels in certain tissues. although findings are conflicting. A better understanding of how PUFAs regulate K_V7 and BK_Ca channels may offer insight into their physiological regulation and may lead to new therapeutic strategies and approaches.