Scottish Secretary Michael Moore, from Cameron's junior coalition partners the Liberal Democrats, will be replaced by Alistair Carmichael, another member of the centrist party.
Deputy Prime Minister Nick Clegg, the Lib Dem leader, said the British government needed to "draw on different experience in the final year running up to the referendum".
The government is pushing for a "no" vote in Scotland's referendum on whether to split from the rest of the United Kingdom, which will be held on September 18 next year.
Scotland's First Minister Alex Salmond, the Scottish National Party leader, is heading up the "yes" campaign.
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Around a third of voters in Scotland are currently in favour of breaking away, according to opinion polls.
Moore is the only member of the cabinet -- comprising Cameron and his 21 most senior ministers -- to be affected by the Conservative premier's second reshuffle since he came to power in May 2010, but the shake-up has led to widespread changes at the lower levels of government.
"The main thing is are they qualified to do the job and I think they will prove that," he added.
The most surprising move was that of Liberal Democrat Norman Baker from the Department for Transport to the Home Office.
Baker once claimed that David Kelly, the government scientist who questioned the evidence used to justify the Iraq War, was murdered and that the security services staged a cover-up.
The reshuffle began on Friday with the resignation of junior transport minister Simon Burns, followed by two other resignations by members of the government on Sunday.
Both Cameron and Clegg are seeking to freshen up their top teams ahead of a general election in May 2015.