Background and Purpose: Spinal muscular atrophy (SMA) is a severe motor neuron disease caused by smn1 loss, leading to reduced survival motor neuron (SMN) protein and progressive motor neuron degeneration. Although SMN-restoring therapies (Spinraza®, Zolgensma®, Evrysdi®) improve outcomes, residual disease burden and non-curative efficacy underscore the need for complementary, SMN-independent treatments. Neuronal hyperexcitability, driven by dysregulated voltage-gated sodium (Na V) channels, has emerged as a key pathogenic mechanism in SMA and a potential therapeutic target. Experimental Approach: We evaluated the therapeutic effects of ProTx-III, a spider-venom peptide selectively modulating Na V gating, and riluzole, an approved anti-excitability drug, in a zebrafish smn1⁻/⁻ SMA model. Behavioural and survival assays assessed in vivo efficacy, and electrophysiological analyses characterised Na V gating modulation, and state- and use-dependent Na V inhibition. Key Results: Pharmacological Na V modulation significantly improved locomotor performance and extended lifespan in smn1⁻/⁻ zebrafish, with superior effects observed for ProTx-III compared to riluzole. In contrast, N-type calcium channel inhibition by ziconotide yielded limited benefit. ProTx-III produced balanced gating shifts across a broad voltage range, preserving physiological excitability, whereas riluzole preferentially stabilised Na V channels in the inactivated state. Both compounds exhibited use-dependent inhibition, increasing affinity for Na V1.2 (riluzole) and Na V1.6 (ProTx-III) during high frequency firing. Conclusions and Implications: Selective Na V channel gating modulation significantly mitigates hyperexcitability, preserves motor function, and prolongs survival in SMA. These findings establish Na V channels as a mechanistically defined, SMN-independent pharmacological target, supporting the potential of selective modulators such as ProTx-III as combined or standalone therapies for SMA and other motor neuron diseases.