Entecavir (ETV) is an antiviral used to treat chronic infection caused by the hepatitis B virus, which affects approximately 250 million people worldwide. In order to mitigate the impacts of ETV on the environment, including potential harm to human health, this study evaluated the use of the Fenton-like reaction, which uses iron complexed with ethylenediaminetetraacetic acid (EDTA) at neutral pH, and the microbiological action of Microcystis novacekii in removing ETV from the aqueous medium. Aqueous concentrations of 100 mg/L were subjected to Fenton-like degradation. Solutions ranging from 1.2 to 120 mg/L were used for biodegradation. The results evidenced consistent effectiveness in completely removing ETV by the Fenton-like reaction after 90 s. However, removal by the action of M. novacekii did not return convincing results. Although entecavir exposure did not affect cyanobacterial cell growth, a gradual reduction in drug content was observed starting on the fourth day of exposure, with maximum removal of 28.9% at the lowest exposure concentration (1.2 mg/L), without, however, showing a significant difference. Statistically significant differences in drug removal were identified only after 14 days of exposure and at specific concentrations. The ETV degradation process through the Fenton reaction was effective and promising for practical application. Removal through M. novacekii showed limited efficacy for practical application for its direct use in the remediation of ETV in aquatic environments. However, we identified a slight decrease in the initial concentrations that could achieve greater efficiency in the drug’s degradation through associations with other microorganisms, physiochemical processes, or even genetic engineering.