To design and synthesis of indole schiff base derivatives and investigate their anti-HIV-1 activities. Indole Schiff base derivatives were synthesized from 3-indole-formaldehyde derivatives by aldehyde-amine condensation with aromatic amines under the catalysis of base. The anti-HIV activities was determined by MTT assays in MT-4 cells.Thirty-two indole schiff base derivatives were synthesized and the structures have been confirmed by 1H NMR and MS spectra. The preliminary biological results showed that all synthesized indole schiff base derivatives had good inhibitory effect on HIV-1 growth, and a broad spectrum of anti-HIV activities. Specifically, compound 31 (EC50 = 0.06 mol/L) exhibited the greatest anti-HIV potency, which was equipotent to reference drug delavirdine. Moreover, the toxicity of compound 31 was very low, and the selectivity index (SI) was as high as 2500, which was significantly higher than that of delavirdine (DLV, SI = 1272.9) and efavirapine (EFV, SI = 321g). Indole and schiff base unit are both important anti-HIV pharmacophore, HIV-1 non-nuclear nucleoside reverse transcriptase inhibitors (NNRTIs) with high efficiency and low toxicity can be obtained by coupling of indole and Schiff base, and this study provides a new idea for the development of new, structurally diverse NNRTIs.