Triple-negative breast cancer (TNBC) has a high incidence of metastasis and limited therapeutic options. Here, we identify a multimodal and targetable miR-342-E2F network that regulates metastatic outgrowth in TNBC. Through integrating clinical and experimental datasets, we uncover miR-342 as a suppressor of TNBC metastasis. Temporal re-expression of miR-342 significantly inhibited metastatic progression in both immunocompetent and xenograft TNBC models by specifically limiting the outgrowth of disseminated tumour cells. Using multi-omics profiling, we identified the global complement of miR-342 targets, demonstrating that it directly suppresses transcriptional and post-transcriptional networks that converge to dampen E2F signaling. Single cell analysis of matched primary and metastatic patient derived TNBC samples reveal activation of E2F signaling in metastasis that corresponds with reduced miR-342 host gene EVL expression. Furthermore, pharmacologic inhibition of this pathway with the CDK4/6 inhibitor palbociclib specifically reduces metastatic outgrowth of pre-established TNBC lesions. Our findings reveal that TNBCs with low miR-342/high E2F signaling have increased metastatic competency and may be amenable to CDK4/6 inhibitor therapy, offering a potential strategy for targeted intervention to limit TNBC metastasis.