Energy consumption and carbon emissions are challenging the current construction industry. The development of plant-based building materials has thus become increasingly crucial, given the high environmental impact of traditional construction materials, such as cement and ordinary concrete. A homogenization model based on multi-scale structural features is proposed to predict, evaluate, and optimize the mechanical and transport properties of a wide range of bio-based materials containing a high volume ratio of plant inclusions. The proposed model involves at different scales the volume fraction of each phase, shape, and orientation of bio-aggregates, different pore sizes, moisture, and imperfect contact, etc. Thanks to a parametric analysis, the multi-scale model optimizes the thermal insulation and mechanical capacities by highlighting the most relevant physical and micro-geometrical characteristics leading to a decrease in the thermal conductivity and an increase of the young modulus of the material understudy. In particular, water saturation and imperfect contact significantly affect the thermal conductivity of bio-based building materials. In detail, imperfect contact has a greater effect perpendicular to the direction of compaction than the parallel direction, increasing the material’s anisotropy. Increasing water content can significantly reduce the thermal insulation of bio-based construction materials. Further, the multi-scale model is used to optimize the combined performance of bio-based concrete through a multi-objective optimization approach to find the best tradeoff between competing objectives. The optimization strategy for bio-based concrete is to find the Pareto optimal solution for multiple application requirements, thus improving the overall performance of bio-based concrete based on different constraints. This work contributes to existing modelling knowledge by considering all of these factors affecting both the mechanical properties and thermal conductivity and by providing a predictive method to optimize the physical and geometrical choice to get the optimal thermal insulation and mechanical requirement. Overall, this study advances the application of plant-based building materials and provides a theoretical basis for the application and optimization of agricultural by-products in the construction industry, thereby potentially contributing to a more sustainable and efficient construction industry.