Clayton is a partner at New York law firm Sullivan & Cromwell, which specialises in advising clients on private and public mergers and acquisitions.
"I look forward to working closely with my fellow commissioners and the dedicated career staff at the SEC to serve the American public and advance the SEC’s important mission," Clayton said in a statement.
President Donald Trump’s nomination of Clayton in January led to questions over conflicts of interest.
In March, Clayton was questioned by the Senate Banking, Housing and Urban Affairs Committee over multiple conflicts of interest, in particular his professional ties to Goldman Sachs, which he represented during the financial crisis.
His wife Gretchen Clayton is vice president of Goldman Sachs.
The US Senate vote, which took place on Tuesday, saw 61 representatives in favour of Clayton’s appointment, with 37 against.
The date for Clayton to be sworn in is yet to be announced. His term will run until June 2021.
He will replace Michael S Piwowar, who was designated acting chairman of the SEC by Trump on 23 January 2017.
Dr Piwowar was first appointed to the SEC by the previous US president, Barack Obama, and was sworn in on 15 August 2013.
The SEC regulates the US stock exchange by enforcing securities law and regulation.