Functional dyspepsia is a form of dyspepsia lacking in clear causes following clinical assessment. Dyspepsia is characterized by episodic or persistent abdominal pain or discomfort of the upper gastrointestinal (GI) tract. Its onset has been linked with a deficiency or dysfunction of digestive enzymes. Thus, consumption of digestive multi-enzymatic preparations may be effectively used for the reduction of symptoms. The aim of this study is to assess the effectiveness and tolerability of the supplementation of a normal diet with a multi-enzyme blend obtained from fungal fermentation, in a randomized, placebo-controlled, double-blind, clinical trial. Enrolled subjects (n = 120, male: 63, female: 57), aged 18–59 years, were randomized (allocation ratio 1:1) to receive either 2 capsules per day of the food supplement (containing 200 mg of the multi-enzyme blend/capsule) or placebo, for 2 months. The primary outcome of the study (i.e., improvements in quality of life) was evaluated by the Nepean Dyspepsia Index-SF (NDI-SF) questionnaire, while the secondary outcomes (i.e., severity of pain and the quality of sleep) were assessed through the Visual Analogue Scale (VAS) and Pittsburgh Sleep Quality Index (PSQI) questionnaire. The results showed an improvement in NDI-SF1, NDI-SF2–5, VAS, and PSQI scores in subjects treated with the multi-enzyme blend, indicating an improvement in quality of life and of sleep, and a decreased severity of pain, following the supplementation with digestive enzymes, without side effects. In conclusion, treatment with digestive enzymes was found to be effective in the reduction of functional dyspepsia symptoms and in the improvement of sleep quality, and is well-tolerated.