Biological matter evolution provides an idea for the human design and synthesis of new materials. However, biomimetic materials only stay in laboratory-scale models, and their large-scale industrial applications are yet to be realized. Here, inspired by nacre’s architecture, we report a continuous, large-scale method to fabricate phosphogypsum composites by reactive extrusion strategy. After curing for seven days, with more than 50 wt% of beta-hemihydrate phosphogypsum (β-HPG), the compressive strength and softening coefficient were 24.98 MPa and 0.78, increasing by 110.0% and 20.0%, respectively, compared to the pouring method. The results show that the screw extrusion process can improve the mechanical strength and waterproof properties of β-HPG hydration specimens without any special chemical admixtures and cements.