Secreted non-structural protein 1 (sNS1) is an important orthoflavivirus pathogenic factor that can induce vascular leakage; a key symptom of severe dengue disease. Given the role of sNS1 in dengue pathogenesis, defining the molecular mechanisms of NS1 secretion may contribute towards development of NS1-targeting antiviral therapies. To this end, we performed a customised membrane-trafficking siRNA screen to identify human host factors involved in NS1 secretion. Our screen identified COPA, COPB2, and COPG1, three of the seven subunits of the coatomer protein complex I (COPI) that coat transport vesicles that operate within the early secretory pathway as the top-ranking hits, heavily implicating COPI machinery as being involved in NS1 secretion. Validation studies employing host gene knockdown in dengue virus (DENV)-infected cells confirmed that COPI components are required for efficient NS1 secretion but are dispensable for infectious virus egress. Similar reductions in NS1 secretion were observed when COPI components were depleted in cells infected with West Nile virus Kunjin subtype (WNV/KUNV), indicating that the molecular mechanisms exploited to achieve NS1 secretion may be a conserved feature within the orthoflavivirus genus. Heterologous expression of wildtype and pathogenic COPI variants in DENV NS1-NS5 polyprotein expressing cells resulted in altered NS1 secretion profiles, suggesting that allelic variants and altered expression levels of COPI components may indirectly influence the severity of dengue disease. The identification of COPI components as important determinants of NS1 secretion efficiency may aid in the identification of novel targets for anti-orthoflaviviral therapies.