Adenosine-to-inosine (A-to-I) RNA editing catalyzed by ADAR1 plays essential roles in the regulation of diverse molecular and cellular processes both under physiological conditions and in the disease states, including cancer. However, mechanisms governing the protein abundance and activity of ADAR1, particularly of its constitutively-expressed and ubiquitous form, ADAR1p110, are largely unknown. Here, we report the E3 ubiquitin ligase SMURF2 as an essential positive regulator of ADAR1p110. We show that SMURF2 directly interacts with ADAR1p110, oligo-ubiquitinates it in an E3 ubiquitin ligase-dependent manner, and stabilizes ADAR1p110 expression by reducing its proteolysis through the proteasomal and lysosomal degradation pathways. The ability of SMURF2 to positively regulate ADAR1p110 was observed in different types of human cells and tissues, and in mouse tissues derived from Smurf2 knock-out and wild-type animals. Further investigations uncovered that SMURF2 regulates ADAR1p110 through its ubiquitination on K744 residue. Mutation of K744 to arginine (K744R), which is also linked to several human disorders, abolished SMURF2-mediated protection of ADAR1p110 from the proteolysis and inactivated its RNA editing activity. Additionally, SMURF2 showed a significant impact on ADAR1p110 protein-protein interactions, influencing its stability and functions. Altogether, these findings reveal SMURF2 as a multilayer regulator of ADAR1p110, governing its protein expression, interactions and functions.