Influenza viruses still represent a great concern for Public Health by causing yearly seasonal epidemics and occasionally worldwide pandemics. Moreover, spillover events at the animal-human interface are becoming more frequent nowadays, also involving animal species not previously found as reservoirs. To restrict the effects of influenza virus epidemics, especially in at-risk population, and to prepare a drug arsenal for possible future pandemics, researchers worldwide have been working on the development of antiviral strategies since the 80's of the last century. One of the main obstacles is the considerable genomic variability of influenza viruses, which constantly poses the issues of drug-resistance emergence and immune evasion. This review summarizes the approved therapeutics for clinical management of influenza, promising new anti-flu compounds and monoclonal antibodies currently undergoing clinical evaluation, and molecules with efficacy against influenza virus in preclinical studies. Moreover, we discuss some innovative anti-influenza therapeutic approaches such as combination therapies and targeted protein degradation. Given the limited number of drugs approved for influenza treatment, there is a still strong need for novel potent anti-influenza drugs endowed with a high barrier to drug resistance and broad-spectrum activity against influenza viruses of animal origin that may be responsible of future large outbreaks and pandemics.