Neuroblastoma is a debilitating illness with a survival rate as low as 40%. It largely impacts young children. Research into an effective treatment is both extensive and ongoing, and a number of potential drug classes have been identified for clinical use. One such promising group of compounds has been shown to target an essential regulatory protein of actin filaments, tropomyosin. More specifically, these anti-tropomyosin drugs (ATMs) target the Tpm3.1 isoform, which is known to be upregulated in cancer cells. We have found that the ATMs synergise with anti-microtubule agents both in vitro and in vivo, improving the efficacy of these compounds by up to 20-fold. This synergy is not seen with other currently used therapeutics for neuroblastoma. Elucidation of the mechanism of synergy has important implications for the translation of this approach into the clinic. Following drug combination treatment of neuroblastoma cells and visualisation of their cytoskeletal networks using high content imaging, our results suggest that synergy is not acting through a general collapse of the microtubule and actin cytoskeletons. Our results show that treatment with both drugs, at levels which have no impact as single agents, causes a G2/M arrest of the cells, suggesting that the ATMs may enhance the mechanism of action of anti-microtubule drugs. Detailed examination of the mitotic events of neuroblastoma lines through cell cycle analysis and immunofluorescent staining has revealed that the synergy appears to result from a block in the transition from prometaphase to metaphase. We propose that microtubules and actin filaments containing Tpm3.1 may collaborate in the mitotic spindle organisation.