Recently, the cultivation of hazel is undergoing a large expansion. Italy is the world’s second largest producer of hazelnuts, with a production of around 98,530 tons in 2019. The processing of hazelnuts produces large amounts of waste, especially woody pericarps, due to the cracking process, generally used for domestic heating, causing air pollution. The high lignin content present in the pericarps makes them a suitable substrate for the cultivation of edible and medicinal mushrooms. To this aim, Ganoderma lucidum, Lentinula edodes, and Pleurotus cornucopiae were grown and cultivated on different hazelnut-shell-based substrates: Hazelnut Shell (HS), Hazelnut Shell and Wheat Straw (HS-WS), and Wheat Straw mixed with Beech Chips (WS-BC) as control. In vitro mycelial grow rate, the degradation capacity of the lignocellulosic fraction, the biological efficiency, and the qualitative differences between mushrooms growing on different substrates by using Attenuated Total Reflectance–Fourier transform infrared (ATR-FTIR) spectroscopy were investigated. Our results suggested the ability of G. lucidum, L. edodes, and P. cornucopiae to grow and decay the lignocellulosic fraction of HS. Cultivation trials showed a similar biological efficiency but a different Fruiting Body Production (FBP) in the presence of HS with respect to the control. ATR-FTIR analysis provided a chemical insight for the examined fruiting bodies, and differences were found among the substrates studied. These results provide attractive perspectives both for more sustainable management and for the improvement of mushroom cultivation efficiency.