Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and causes a high rate of mortality in affected adults. Many subtypes of ALL exist with disruptions in distinct genetic pathways, including those regulated by miRNAs. Here we identify miR-187-5p as being highly upregulated in B-cell ALL and a driver of cellular proliferation and suppressor of apoptosis. We show that miR-187-5p directly targets the 3'-UTR of DKK2 to mediate these effects. We further determine that inhibition of DKK2 by miR-187-5p in Nalm-6 B cells leads to inappropriate activation of Wnt/β-catenin signaling. Together, these findings reveal that the miR-187-5p-DKK2 pathway regulates Wnt/β-catenin signaling, cell growth, and apoptosis. Our findings provide the first evidence of a role for miR-187-5p in promotion of B-cell ALL.