ABSTRACT: Introduction: HIV-1 infection is considered one of the major public health problems worldwide. Due to the limited access to antiretroviral therapy, the associated side effects, and the resistance that the virus can generate, it has become necessary to continue the development of new antiviral agents. Natural products and their derivatives have shown therapeutic potential against HIV-1, including zidovudine, bevirimat, calanolide A, among others. The present study aimed to identify the anti-HIV-1 potential (in vitro and in silico) of sixteen synthetic di-halogenated compounds derived from L-Tyrosine. Methodology: toxicological modeling was performed with ADMET Predictor® and molecular docking with viral proteins was evaluated in silico using Autodock Vina®. In vitro cytotoxicity was determined by MTT in the TZM-bl cell line. A combined antiviral screening strategy (pre- and post-infection treatment) was performed in HIV-1 infected TZM-bl cells (R5 and X4 strains). The inhibitory effect was quantified by luciferase activity. Moreover, the antiviral activity of the most promising compounds against a pseudotyped virus (HIV-GFP-VSV-G) was determined by flow cytometry. Results: lower toxicity (both in silico and in vitro) of L-tyrosine-derived compounds was observed for those compounds with the free OH compared to tyramine-derived compounds. The compounds TODB-2M, TODC-2M, TODC-3M and YDC-3M showed statistically significant inhibitory activity greater than 40% against HIV-1 strains X4 and R5, and greater than 12% against HIV-GFP-VSV-G virus. Finally, in silico results showed favorable binding energy, mainly with protease, reverse transcriptase or gp120. Conclusion: compounds TODB-2M, TODC-2M, TODC-3M and YDC-3M have antiviral potential against HIV-1. The antiviral activity may be due to interaction with reverse transcriptase and/or viral protease, or with envelope gp120.