The dataset contains B, Li, Mg and Sr concentrations and isotopic compositions of black-smoker, acid-sulfate fluids and "hybrid-types" as well as of fresh and altered rocks from different vent fields (DESMOS and North Su) within the Manus Basin, Papua New Guinea. The data is used to understand the controls of their compositional variability. In particular, the formation of acid-sulfate and hybrid smoker fluids is still poorly understood, and their high Mg concentrations are explained either by dissolution of Mg-bearing minerals in the basement or by mixing between unmodified seawater and magmatic fluids. Mg isotope ratios of the acid-sulfate fluids from Manus Basin are seawater-like, which supports the idea that acid-sulfate fluids in this study area predominantly form by mixing between unmodified seawater and a Mg-free magmatic fluid. Changes in the B, Li, and Sr isotope ratios relative to seawater indicate water-rock interaction in all acid-sulfate fluids. Further, the combination of δ7Li with B concentrations of the same fluids links changes in δ7Li to changes in (1) basement alteration, (2) water-to-rock ratios during water-rock interaction and/or (3) the reaction temperature. These isotope systems, thus, allow tracing of basement composition and acid-sulfate driven alteration of the backarc crust, and help increase our understanding of hydrothermal fluid-rock interactions and the behavior of fluid-mobile elements.