His ban is effective from Friday, with credit for the provisional suspension he served between April 12th and June 19th last year, preventing the 21-year-old from competing at the upcoming World Championships in Tokyo.
Knighton, a 200 metres world silver medallist in 2023, was charged with an ADRV in May 2024 when an out-of-competition doping test revealed the presence of Epitrenbolone, an anabolic steroid on WADA's prohibited list.
The US Anti-Doping Agency (USADA) attempted to sanction Knighton, but an Arbitration Tribunal said he should not be banned as he bore no fault or negligence in connection with the use and presence of the substance.
The decision had cleared him to compete in the US Olympic trials.
However, World Athletics and the global anti-doping body appealed to sport's highest court against USADA and Knighton to set aside the Tribunal's decision and both appeals were considered jointly.
"WA and WADA considered that the evidence submitted by the athlete and his explanations of a meat contamination scenario fell short of the required proof of source and were statistically impossible," CAS said in a statement.
"Knighton argued that the ADRV was caused by the ingestion of an oxtail dish contaminated with trenbolone."
Trenbolone is a known livestock growth promoter used legally in beef cattle produced in and exported to the United States.
"The CAS Panel determined that there is no proof that would support the conclusion that oxtail imported into the USA would be likely to contain trenbolone residues at the level required to have caused the athlete's Adverse Analytical Finding," it added.
Although CAS upheld the appeal for a four-year ban, they only partially granted their request to disqualify all his results since March 2024. He has been disqualified retroactively from March 26th to April 12th, 2024.