The c-Myc transcription factor activates a cascade of downstream targets to form a complex transcriptional program that ultimately leads to cellular transformation. Although a large number of protein-encoding genes as well as non-coding RNAs were identified as Myc targets, only a few have been validated to be functionally important for c-Myc-driven transformation. Here, we identify a microRNA (miRNA), miR-378, as a novel target of the c-Myc oncoprotein that is able to cooperate with activated Ras or HER2 to promote cellular transformation. Mechanistically, miR-378 achieves this oncogenic effect, at least in part, by targeting and inhibiting the anti-proliferative BTG family member, TOB2, which is further elucidated as a candidate tumor suppressor to transcriptionally repress proto-oncogene cyclin D1. Therefore, our study identifies miR-378-TOB2-cyclin D1 as a functional module to mediate the cross talk between Myc and Ras signaling in cellular transformation.