A chemical library comprising 2,354 drug-like compounds was screened using a transcription and replication-competent virus-like particle (trVLP) system that implements the whole Ebola virus (EBOV) life cycle. Dose-dependent inhibition of Ebola trVLP replication was induced by 15 hit compounds, which target different kinds of G protein-coupled receptors (GPCRs) mainly. Based on the chemical structures, they were divided into three groups, diphenylmethane derivatives, promazine derivatives or without any core skeletons. Within the third group, sertindole, raloxifene, and ibutamoren showed prominent antiviral effects in cells. They down-regulated expression of viral proteins, including the VP40 matrix protein and the envelope glycoprotein, and also reduced the amount of EBOV-derived tetracistronic minigenome RNA incorporated into progeny trVLPs in the culture supernatant. Particularly, ibutamoren, known as an agonist of growth hormone secretagogue receptor (GHSR), showed the most promising antiviral activity with a 50% effective concentration of 0.2 μM, a 50% cytotoxic concentration of 42.4 μM, and a selectivity index of 222.8. Here, we suggest that agonistic molecules to GHSR could be developed as anti-EBOV therapeutics.