Armstrong, who retired last year, declined to enter arbitration - his last option - because he said he was weary of fighting accusations that have dogged him for years. He has consistently pointed to the hundreds of drug tests that he has passed as proof of his innocence.
"There comes a point in every man's life when he has to say, 'Enough is enough.' For me, that time is now," Armstrong said in a statement sent to the Associated Press. He called the USADA investigation an "unconstitutional witch hunt."
"I have been dealing with claims that I cheated and had an unfair advantage in winning my seven Tours since 1999," he said. "The toll this has taken on my family and my work for our foundation and on me leads me to where I am today - finished with this nonsense."
USADA will almost certainly treat Armstrong's decision as an admission of guilt, and hang the label of drug cheat on an athlete who was a hero to thousands for overcoming life-threatening testicular cancer and for his foundation's support for cancer research.
The agency can impose a lifetime ban and recommend Armstrong be stripped of his titles. That would put the question in the hands of the International Cycling Union, which has disputed USADA's authority to pursue the investigation and Tour de France officials, who have had a prickly relationship with Armstrong over the years.
Armstrong, 40, insisted his decision is not an admission of drug use, but a refusal to enter an arbitration process he believes is improper and unfair to athletes facing charges.