It is a grand challenge to develop a truly effective treatment of substance use disorder (SUD), particularly for cocaine and other drugs without an FDA-approved treatment available, because a truly effective therapy must effectively block the drug's physiological and reinforcing effects during the entire period of treatment in order to achieve the long-time abstinence required by the FDA. Whether a biologic, such as monoclonal antibody, vaccine, or therapeutic enzyme, can be truly effective for SUD treatment or not has been the subject of extensive debate. The main debate question is whether a biologic, particularly an exogenous enzyme, can effectively block the drug's reinforcing effect. In this report, we demonstrate that a modest dose of a recently redesigned long-acting cocaine hydrolase, CocH3-Fc(M6), can be used to effectively block the psychostimulant, discriminative stimulus, and reinforcing effects of cocaine for a sufficiently long period of time. For example, a dose of 3 mg/kg CocH3-Fc(M6) completely blocked the discriminative stimulus and reinforcing effects for 24/25 days and continued to significantly attenuate/decrease the cocaine effects for at least 29 days in rats. All the animal data consistently suggest that the long-acting cocaine hydrolase is a truly promising candidate of enzyme therapy for treatment of cocaine use disorder. •There is no FDA-approved medication specific for cocaine overdose or dependence.•It is challenging to block effects of cocaine without affecting normal function of brain.•Accelerating cocaine hydrolysis is recognized as a promising therapeutic strategy.•An enzyme is capable of long-lasting blocking of cocaine discrimination in rats.•The enzyme is capable of long-lasting blocking of cocaine self-administration in rats.