Dengue virus (DENV) is the most common mosquito-borne viral disease and is responsible for a major public health burden in tropical and subtropical regions around the world. Despite this, there are no approved antiviral therapeutics available. We sought to discover novel inhibitors of DENV non-structural protein 1 (NS1), using a Nanoluciferase-based thermal shift assay in conjunction with a Nanoluciferase-tagged dengue reporter virus (DENV2-NS1-NLuc) in a high-throughput compound screen of 3,378 drug-like compounds. While we were unable to unambiguously identify NS1-targeting compounds, ‘hit’ compound validation studies revealed a collection of structurally related compounds which inhibit DENV infection in a hepatoma cell culture model. Following testing of 40 structurally related analogues, we identified a top hit (PubChem CID: 50839998) which had minimal impact on viral RNA replication and cell viability but inhibited infectious particle production at low micromolar concentrations. Examination of the impact of this compound on viral protein localization profiles by confocal microscopy revealed dose-dependent reductions in the abundance of the viral Envelope (E) protein, consistent with the observed inhibition of infectious virus production. Further investigation into the mechanism of action of this compound is warranted to determine its exact molecular target(s), while testing of a wider range of structural analogues may enable identification of related compounds with greater efficacy and lower cytotoxicity.