A grand jury spent more than three months reviewing evidence in the case before declining in November to issue any charges against Wilson. He told jurors that he feared for his life when Brown hit him and reached for his gun.
The U.S. Justice Department is still conducting a civil rights investigation into the shooting and a separate probe of police department practices.
The shooting struck up a national debate about race and police power.
After the shooting, Wilson spent months in hiding and made no public statements. He broke his silence after the grand jury decision, telling ABC News that he could not have done anything differently in the encounter with Brown.
Wilson said he has a clean conscience because "I know I did my job right." Brown's shooting was the first time he fired his gun on the job, he said.
Asked whether the encounter would have unfolded the same way if Brown had been white, Wilson said yes.
Wilson began his career in nearby Jennings before moving to the Ferguson job a few years ago. He had no previous complaints against him and a good career record, according to Police Chief Thomas Jackson, who called Wilson "an excellent police officer."
A few months before the shooting, Wilson had received a commendation for detaining a suspect in a drug case.
Read Darren Wilson's resignation letter, via St. Louis Post-Dispatch:
"I, Darren Wilson, hereby resign my commission as a police officer with the City of Ferguson effective immediately. I have been told that my continued employment may put the residents and police officers of the City of Ferguson at risk, which is a circumstance that I cannot allow. For obvious reasons, I wanted to wait until the grand jury made their decision before I officially made my decision to resign. It was my hope to continue in police work, but the safety of other police officers and the community are of paramount importance to me. It is my hope that my resignation will allow the community to heal. I would like to thank all of my supporters and fellow officers throughout this process."