Neuroblastoma is the most common extracranial solid tumour in childhood. Prognosis in the high-risk cases remains poor, highlighting the need for novel therapies. Neuroblastomas are characterised by a fundamental downregulation of mitochondrial respiration and a high glycolytic rate. This is due to genomic aberrations such as MYCN gene amplification and loss of chromosomal regions encoding succinate dehydrogenase subunits. This phenotype causes an increased reliance on pH-regulatory proteins, monocarboxylate transporters (MCTs) 1–4 and carbonic anhydrases (CAs) to maintain metabolic homeostasis. Myc has been linked to MCT-1 and CAIX expression and thus it was hypothesised that neuroblastomas would be sensitive to inhibition of these proteins. AZD3965 is a Phase I clinical candidate for MCT-1 inhibition whereas indisulam is a widely known Phase II clinical candidate for CAIX inhibition. As expected, MCT-1 inhibition blocked glycolysis and caused growth inhibition in 2-dimensional (-D) neuroblastoma models. However, there was a rapid onset of metabolic adaptation and 3-D spheroids were resistant. This resistance was overcome by combining MCT-1 inhibition with metformin, a mitochondrial complex I inhibitor. However, other adaptive mechanisms were also identified in 2-D. In contrast, we present a novel finding that indisulam monotherapy is efficacious in neuroblastoma, in vitro and in vivo. Notably, indisulam did not decrease the glycolytic rate as expected of a CAIX inhibitor. Instead, indisulam decreased cellular spare respiratory capacity and induced metabolic alterations associated with mitochondria. Consistent with a respiratory inhibitor, indisulam was also shown to synergise with MCT-1 inhibition, like metformin. In addition, indisulam recruited the RNA splicing factor and transcriptional coactivator, CAPERα, for proteasomal degradation and induced RNA splicing defects in neuroblastoma cells. Selective interference of CAPERα phenocopied the loss of respiratory capacity induced by indisulam. Thus, we propose that indisulam is a dual-inhibitor of mitochondrial metabolism and RNA splicing, serving as a novel therapeutic strategy in neuroblastoma.