Abstract Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder caused by mutation of the survival motor neuron 1 (SMN1) gene. SMA is characterized by degeneration of the spinal cord motor neurons caused by chronic low levels of survival motor neuron (SMN) protein. Prevention or slowing of neurodegeneration has been shown to ameliorate SMA disease severity. Significant progress has been made to develop SMN-dependent treatments that increase SMN levels. However, there is an unmet need to develop alternative therapeutic methods that are SMN-independent. The c-Jun-NH2 terminal kinase (JNK) signalling pathway mediates motor neuron degeneration in SMA. Genetic inactivation of the neuron-specific isoform, JNK3, ameliorates the disease phenotype in SMA mice without affecting SMN protein levels, indicating that JNK3 may represent a promising SMN-independent target for pharmacological intervention. We report that pharmacological inhibition of JNK using novel drug compounds based on three distinct chemical scaffolds, Anthrapyrazolone, Pyrimidinyl, and Pyridopyrimidine, prevents degeneration of SMN-deficient in vitro cultured primary cerebellum neurons and the spinal cord motor neurons derived from SMA mice. Furthermore, in vivo treatment with JNK inhibitors leads to a systemic improvement in the disease phenotype, promoting enhanced overall growth, including increased body weight and extended postnatal growth, alongside improved gross motor functions such as righting reflexes and the ability to walk until the later stages of survival. Notably, it also results in a significant and sustained increase in the lifespan of both male and female SMA mice. The sex-based analysis reveals male- and female-specific improvements that depend on the type and efficacy of inhibitors targeting distinct JNK isoforms. Importantly, treatment with JNK inhibitors did not affect SMN levels in the spinal cord or skeletal muscle, indicating that the observed rescue of the SMA phenotype occurs independently of SMN restoration. Collectively, these findings suggest that pharmacological inhibition of JNK may serve as a therapeutic strategy to prevent neurodegeneration, either in combination with SMN-enhancing approaches for treating severe forms of SMA, or as a stand-alone, SMN-independent intervention for moderate and mild SMA cases.