The Keketale is the largest Pb–Zn deposit in the volcano‐sedimentary Maizi Basin of the South Altay Orogenic Belt (AOB), Northwest China. The stratabound orebodies are hosted in a suite of meta‐sedimentary rocks intercalated with volcanic rocks of the Lower Devonian Kangbutiebao Formation. The massive and banded ores representing the main mineralization stage are relatively well‐preserved in the ore district. This paper reports systematic geochronological results including the zircon laser ablation–multiple collector–inductively coupled plasma–mass spectrometry (LA‐MC‐ICP‐MS) U–Pb analyses on two meta‐felsic volcanic rocks from the Kangbutiebao Formation and Rb–Sr isotope dating on seven sphalerite samples from the main mineralization stage, together with some sulphur isotopic data to constrain the mineralization age and the genesis of the deposit. Rb–Sr isotope dating yield an isochron age of 398.2 ± 3.3 Ma generally synchronous with the zircon (LA‐MC‐ICP‐MS) U–Pb analyses of a meta‐rhyolite and a meta‐dacite from the strata (410.5 ± 1.3 Ma and 394.8 ± 1.9 Ma, respectively). The δ34S values of seven pyrite samples in the main massive and banded ores vary from −12.4‰ to −6.2‰, indicating that the main ore‐forming sulphur of the deposit was derived from bacterial reduction of seawater sulphate. By integrating the field, chronological, and isotopic evidences, we conclude that the Keketale Pb–Zn deposit is a VMS‐type deposit. Combining our results with the isotopic geochronology in the South AOB, we argue that the South AOB has undergone three mineralization episodes: the syndepositional mineralization (412–387 Ma), the subvolcanic hydrothermal‐related mineralization (382–379 Ma), and the epigenetic mineralization that is genetically linked to regional metamorphism and deformation (260–204 Ma). The Keketale Pb–Zn deposit is a product of the Devonian seafloor hydrothermal exhalation system in the South AOB.