Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression. The lymphatic system, whichplays a critical role in cancer prognosis, is innervated by fibers of the SNS. However, the effect of SNS signalling on lymphatic function and the consequences for cancer progression are unknown. Here, we show that stress acts via the SNS to impact lymphatic function by restructuring lymphatic vasculature and modulating lymph flow to provide pathways for tumour cell escape. Using multiple preclinical models we show chronic stress remodels intratumoural and tumour-draining lymphatic vessels through a tumour neural-inflammatory axis. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling with beta-blockers blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. We provide clinical evidence that SNS-targeted anaesthetic agents may also be leveraged to modulate lymph flow in patients with cancer. These findings demonstrate an instrumental role for stress SNS signalling in controlling lymphatic function, and reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a novel strategy to improve cancer outcomes.