Dengue is a viral disease caused by the dengue virus (DENV), which continues to pose a significant global public health challenge. This concern is particularly heightened by the rising incidence of dengue over the last two decades. While many infected individuals experience mild symptoms, a subset can progress to severe dengue, characterized by life-threatening hemorrhagic complications. Addressing this critical public health issue requires the development of new, safe, and effective treatments. In this study, the therapeutic potential of various metformin and phenformin analogs against DENV infection was evaluated. The antiviral effect was assessed by measuring the percentage of infected cells, as well as the levels of viral proteins and infectious viral particles. Additionally, DENV-infected AG129 mice were treated with two selected analogs and monitored for survival, weight changes, clinical signs, and viral RNA copies. The results demonstrated that these analogs effectively inhibited the number of infected cells, reduced viral protein levels, and decreased the formation of infectious viral particles. Furthermore, when compared to metformin (MET), certain analogs exhibited enhanced antiviral efficacy. Notably, we also found that the antiviral activity of the analogs correlated with increased levels of phosphorylated AMPK (pAMPK). In vivo treatments yielded significant antiviral effects, as evidenced by reduced clinical symptoms, lower mortality rates compared to untreated controls, and a marked reduction in viral load. These findings underscore the potential of biguanides derivatives as promising therapeutic agents against dengue infection, providing a foundation for further exploration of their antiviral properties.