The RNA helicase Moloney leukemia virus 10 (MOV10) is involved in several RNA processing pathways, including RNA silencing, defense against viral RNA and nonsense-mediated mRNA decay (NMD). MOV10 is a member of the Up-frameshift 1 (UPF1)-family of superfamily 1 (SF1) helicases and like its prototype member, unwinds RNA duplexes bearing a 5'-single-stranded overhang. Sequence comparisons of MOV10 and UPF1 revealed significant identity between their RecA domains and considerable divergence between the N-terminal domains preceding the helicase core. Using in vitro biochemical approaches, we show that the N-terminal domain of MOV10 is functionally distinct from the CH domain of UPF1, both in terms of its impact on catalytic activity and the protein-protein interactions it mediates. MOV10 engages the NMD factor UPF2 via its N-terminal regulatory domain but binds a different region than the UPF1-CH domain. We propose that the interactions mediated by the MOV10-N-terminal domain dictate its localization to cytoplasmic RNA condensates such as P-bodies and stress granules. This is distinct from UPF1, whose localization appears to be driven by its interaction with RNA. Taken together, our work presents a mechanistic model for the recruitment and involvement of MOV10 in NMD, where it was proposed to act as an RNA clearance factor for UPF1.