Background The import of wheat flour is the major driver for the high prices and low use of bakery products in non-producing tropical countries such as the Democratic Republic of Congo (DRC). These products’ high prices worsen the risk of malnutrition and food insecurity among rural and resource-poor populations. This study aimed at substituting the imported wheat flour with less expensive local cassava flour fortified with oyster mushroom flour in order to mitigate the nutritional crisis in the region. Methodology Series of experiments were conducted by substituting wheat flour with cassava flour at proportions of 10–25% to find the optimal combination. In addition, oyster mushroom flour (2.5–10%) was added to the composite flour to compensate for nutrient deficiencies of cereals and tuber crops. The overall aim was to identify the optimal wheat–cassava–mushroom combination, improving the nutritional value of breads while keeping their physico-chemical and organoleptic properties. Results Results showed that 0–10% mushroom flour increased bread protein from 19.63 to 22.66%. Besides, 7.5% mushroom flour allowed rising the bread calories from 311.8 to 354.5 kcal, and the dry matter from 77.33 to 87.86%. The wheat substitution for cassava fortified with mushroom flour negatively affected the bread volume, color and taste (p < 0.001). However, other organoleptic features remained unchanged. The different breads were microbiologically stable for bacteria, but susceptible to fungal attacks. Conclusion This study recommended 5–15–80% and 10–10–80% mushroom–cassava–wheat composite flour for better bakery results, good consistency and high protein and energy contents, for improving the nutritional status of populations in the tropical non-wheat producing regions such as DRC. Efforts are necessary to improve the taste and color of the mushroom-fortified bread to increase its uptake and competitiveness in the local markets.