Domain-specific languages (DSLs) play an increasingly important role in the generation of high performing software. They allow the user to exploit domain knowledge for the generation of more efficient code on target architectures. Here, we describe a new code generation framework (NMODL) for an existing DSL in the NEURON framework, a widely used software for massively parallel simulation of biophysically detailed brain tissue models. Existing NMODL DSL transpilers lack either essential features to generate optimized code or capability to parse the diversity of existing models in the user community. Our NMODL framework has been tested against a large number of previously published user models and offers high-level domain-specific optimizations and symbolic algebraic simplifications before target code generation. NMODL implements multiple SIMD and SPMD targets optimized for modern hardware. When comparing NMODL-generated kernels with NEURON we observe a speedup of up to 20 × , resulting in overall speedups of two different production simulations by ∼7× . When compared to SIMD optimized kernels that heavily relied on auto-vectorization by the compiler still a speedup of up to ∼2× is observed.