The chemical weathering (CW) of rocks at the Earth's surface plays a key role in the global carbon cycle along multiple pathways. Although karst systems are hotspot carbonated areas, they are not always monolithological. It is therefore challenging to estimate the CW of these complex areas. The interannual, seasonal, and spatial variations of CW rates and CO2 consumption were investigated using a long-term hydrogeochemical database (1994–2019) from a mountainous karstic catchment in southwestern France (Baget Catchment). A geochemical and isotopic spatial sampling allowed the identification of the main mineral or lithological sources in the catchment, which controlled the water chemistry. The CW budget showed that the (Ca2+ + Mg2+) fluxes originated from carbonate dissolution (1.14 mol·m−2·yr−1 equivalent to 74%) and silicate weathering (18%) by carbonic acid solutions. Gypsum dissolution and carbonate weathering by sulphuric acid from pyrite oxidation contribute equally to 4%, although the former accounts for 66% of the dissolved sulphate fluxes. During a summer sampling survey, an innovative sulphur isotopic approach based on δ34SSO4, allowed us to demonstrate that the ore-nature sulphuric acid drove 9.0% of total carbonate dissolution and represented only 16.8% of the dissolved sulphate stream fluxes. Hydrological conditions, temperature, vegetation, the epikarst (quasi-permanent shallow and discontinuous saturated layer under the soil), and the water dynamics were the key factors influencing the inter-annual and inter-seasonal variations of the CW rates and CO2 consumption. In addition, the carbon isotopic signature evidenced geochemical processes such as CO2 outgassing and calcite precipitation processes. The latter could remove up to 74% of HCO3− from streamwaters, depending on the hydrological conditions at the outlet between 2016 and 2019. Finally, this study highlights that CW rates and CO2 consumption may vary over inter-annual and inter-seasonal scales, and spatially even for a small catchment. Furthermore, the global CO2 consumption appears to be mainly driven by the runoff intensity in karst hydrosystems, where carbonate dissolution was found to consume 71% of the total weathering CO2 uptake.