Limited clinical data can be found concerning the utility of multikinase inhibition in neuroblastoma. Repotrectinib (TPX-0005) is really a multikinase inhibitor that targets ALK, TRK, JAK2/STAT, and Src/FAK, that have all been implicated within the pathogenesis of neuroblastoma. We evaluated the preclinical activity of repotrectinib monotherapy and in conjunction with chemotherapy like a potential therapeutic method for relapsed/refractory neuroblastoma. In vitro sensitivity to repotrectinib, ensartinib, and cytotoxic chemotherapy was evaluated in neuroblastoma cell lines. In vivo antitumor aftereffect of repotrectinib monotherapy, and in conjunction with chemotherapy, was evaluated utilizing a genotypically diverse cohort of patient-derived xenograft (PDX) types of neuroblastoma. Repotrectinib had comparable cytotoxic activity across cell lines regardless of ALK mutational status. In conjunction with chemotherapy shown elevated antiproliferative activity across several cell lines. Repotrectinib monotherapy had notable antitumor activity and prolonged event-free survival in contrast to vehicle and ensartinib in PDX models (P < 0.05). Repotrectinib plus chemotherapy was superior to chemotherapy alone in ALK-mutant and ALK wild-type PDX models. These results demonstrate that repotrectinib has antitumor activity in genotypically diverse neuroblastoma models, and that combination of a multikinase inhibitor with chemotherapy may be a promising treatment paradigm for translation to the clinic.