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Designing multi-floor arrangements for biodiesel production facilities that utilize empty fruit bunch (EFB) feedstock represents a computationally intensive, large-scale problem that requires the concurrent assessment of cost, hazard mitigation, and building integrity constraints. The present work proposes a Mixed-Integer Nonlinear Programming (MINLP) formulation tailored to multi-level plant layouts, jointly determining optimal equipment materials, vertical floor allocations, sectional positioning, and passive safeguarding features based on explicit safety quantification. Developed within the General Algebraic Modeling System (GAMS) environment, the model is tackled through a staged decomposition consisting of three sequential phases—(i) choice of construction materials together with load-bearing evaluation, (ii) intra-section multi-floor arrangement, and (iii) full-plant sectional coordination—because solving the full monolithic MINLP violates academic solver license restrictions and does not reach convergence under realistic time constraints. In contrast, the sequential procedure consistently delivers solutions featuring small optimality gaps (overall CPU usage: 22.97 min). Applied to a 1,000 t/d EFB processing scenario involving 57 equipment units distributed across seven functional sections, the resulting layout achieves a 28.9% reduction in total capital expenditure, a 51.97% decrease in required land area, and—when separations follow Dow’s Fire and Explosion Index (F&EI) guidelines including credit for installed devices—a 18.8% drop in Maximum Probable Property Damage (MPPD) before protective measures and a 69.0% reduction once protection is accounted for. This hierarchical decomposition technique shows that highly complex facility layout tasks incorporating formal safety limits can be addressed in a tractable and effective manner, supplying a generalizable methodology suitable for diverse multi-objective design problems encountered in the chemical processing and renewable energy domains.