The continuous increase in biogas production poses the need for innovative applications for its by-products. Solid-state fermentation (SSF) has regained attention in the development of several products because of the possibility to use low-cost and easily available substrates, such as organic wastes. SSF represents a valuable process for agricultural digestate valorization in terms of enzyme production. In the present study, cellulase and esterase were produced by Trichoderma asperellum R on a digestate-based substrate in SSF, with esterase as the highest obtained activity. After assessing the effect of light on it, the esterase production in SSF was optimized using response surface methodology. The influence of substrate composition, temperature and humidity on the enzyme production was evaluated on two sets of data generated based on digestate concentration (50% and 70% w/w). The statistical analyses revealed that these parameters affected esterase production only when Trichoderma asperellum grew on substrate containing 50% w/w of digestate. The best esterase activity (264.6 mU/mg total protein) was achieved with the following optimized SSF parameters: 50% digestate, 50% fruits, 10% sawdust, 30 °C. The current finding of esterase production on digestate-based substrates makes the SSF method presented here a sustainable and completely circular technology.