Long-term effects of climate change on lakes globally will include a substantial modification in the thermal regime and the oxygen solubility of lakes, resulting in the alteration of ecosystem processes, habitats, and concentrations of critical substances. Recent efforts have led to the development of long-term model projections of climate change effects on lake thermal regimes and oxygen solubility. However, such projections are hardly ever confronted with observations extending over multiple decades. Furthermore, global-scale forcing parameters in lake models present several limitations, such as the need of significant downscaling. In this study, the effects of climate change on thermal regime and oxygen solubility were analyzed in the four largest French peri-alpine lakes over 1850–2100. We tested several one-dimensional (1D) lake models' robustness for long-term variations based on up to 63 years of limnological data collected by the French Observatory of LAkes (OLA). Here, we evaluate the possibility of forcing mechanistic models by following the long-term evolution of shortwave radiation and air temperature while providing realistic seasonal trends for the other variables for which local-scale downscaling often lacks accuracy. Based on this approach, MyLake, forced by air temperatures and shortwave radiations, predicted accurately the variations in the lake thermal regime over the last 4 to 6 decades, with RMSE < 1.95 ∘C. Over the previous 3 decades, water temperatures have increased by 0.46 ∘C per decade (±0.02 ∘C) in the epilimnion and 0.33 ∘C per decade (±0.06 ∘C) in the hypolimnion. Concomitantly and due to thermal change, O2 solubility has decreased by −0.104 mg L−1 per decade (±0.005 mg L−1) and −0.096 mg L−1 per decade (±0.011 mg L−1) in the epilimnion and hypolimnion, respectively. Based on the shared socio-economic pathway SSP370 of the Intergovernmental Panel on Climate Change (IPCC), peri-alpine lakes could face an increase of 3.80 ∘C (±0.20 ∘C) in the next 70 years, accompanied by a decline of 1.0 mg L−1 (±0.1 mg L−1) of O2 solubility. Together, these results highlight a critical alteration in lake thermal and oxygen conditions in the coming decades, and a need for a better integration of long-term lake observatories data and lake models to anticipate climate effects on lake thermal regimes and habitats.