The increasing availability of agro-industrial side streams has intensified the search for sustainable biotechnological approaches capable of generating added value while reducing waste. Solid-state fermentation (SSF) is recognized as an efficient microbial process for upgrading agricultural residues into valuable products using limited water and energy resources. Within the Pomacle–Bazancourt biorefinery ecosystem in France, large quantities of agricultural by-products are generated and represent promising feedstocks for bio-based applications. Rapeseed cake, hemp oil cake, wheat and alfalfa by-products, and sugar beet pulp were investigated as substrates for SSF. Selected microbial strains were evaluated in combination with physical and chemical pretreatments. Fermentation trials were initially conducted in Erlenmeyer flasks and subsequently transferred to packed-bed bioreactors. Microbial growth, heat production, and mass transfer phenomena were monitored throughout the process. In parallel, Digital Twin simulations were used to support process optimization and evaluate scale-up potential. The investigated side streams supported efficient microbial growth and bioconversion. SSF enabled the generation of value-added products, including bioactive compounds, vitamins, enzymes, natural pigments, flavoring agents, and biomaterials. These products demonstrated potential relevance for several industrial sectors, including food, feed, cosmetic, and textile applications. Process optimization focused on improving productivity while maintaining technical and industrial feasibility. A complementary market-oriented analysis was also performed to assess valorization opportunities. The findings demonstrate the potential of SSF as a sustainable biomass-upgrading strategy for transforming agro-industrial side streams into value-added products. By supporting resource efficiency and biomass valorization, SSF contributes to the development of circular bio-based value chains and offers a sustainable pathway for future food and bio-based production systems.