Numerous studies have reported Up-frameshift protein 1 (UPF1) as a crucial posttranscriptional regulator in nonsense-mediated mRNA decay (NMD), attributing its role to tumorigenesis across various cancers. However, its recently unveiled function in UPF1-mediated mRNA decay (UMD), intricately coordinated with miRNA, remains unexplored in the context of tumorigenesis. Here, we demonstrate that UPF1 contributes to melanoma tumorigenesis by regulating NANOS1 expression in a miR-101-3p-dependent manner. Depletion of UPF1 across three melanoma cell lines significantly impaired cell growth, migration, and invasion by cell cycle arrest and disrupted tumor formation in vivo. Through comprehensive RNA-seq and biochemical analyses, we elucidate that attenuation of UPF1 leads to an increase in NANOS1 expression, consequently suppressing melanoma tumorigenesis. Mechanistically, UPF1 orchestrates the destabilization of NANOS1 via UPF1-mediated mRNA decay (UMD) facilitated by miR-101-3p. Intriguingly, UPF1 depletion and NANOS1 upregulation were associated with reduced ERK and ELK1 phosphorylation, suggesting that attenuation of MAPK/ERK/ELK1 signaling may contribute, at least in part, to the observed melanoma-suppressive phenotypes. Importantly, the biological relevance of UPF1 and NANOS1 in melanoma cell lines was further supported in drug-resistant melanoma cells and in xenograft mouse models. Collectively, these findings expand our understanding of UMD in melanoma and identify the UPF1/NANOS1 regulatory relationship as a potential therapeutic vulnerability in both parental and drug-resistant melanoma cells.