Robert Gates said the spending squeeze would mean the UK could no longer be a full military partner of the US.
Under the government's plans, by 2020 the Army will lose 20,000 personnel, the Royal Navy 6,000 and the RAF 5,000.
The Ministry of Defence says Britain still has the fourth largest defence budget in the world.
It also has “the best-trained and best-equipped armed forces outside the US”, the MoD added in a statement.
But Mr Gates, who served under presidents Obama and Bush, singled out cuts to the navy as particularly damaging.
Interviewed by BBC Radio 4's Today programme, he noted that – for the first time since World War One – Britain did not have an operational aircraft carrier.
“With the fairly substantial reductions in defence spending in Great Britain, what we're finding is that it won't have full spectrum capabilities and the ability to be a full partner as they have been in the past,” he said.
The spectrum refers to the ability of a country's military to fight across air, sea and land.
Mr Gates's comments echo the concerns of other senior military figures.
The Chief of the Defence Staff, General Sir Nicholas Houghton, warned last month Britain could be left with the “spectre” of a hollowed-out force.
Prime Minister David Cameron insisted in 2011 the UK retained a “pretty full spectrum capability” after the three service chiefs warned its reach would be diminished.
Jonathan Beale, the BBC's defence correspondent said the American's latest intervention would be unlikely to reverse the cuts but would wound Britain's pride.
In its statement the MoD said: “Over the next decade, we plan to spend £160bn on equipment, to ensure our armed forces retain their formidable range of cutting-edge capabilities and ability to project power across the globe, including by maintaining our major naval presence in the Gulf Region.
“Construction of the first new aircraft carrier, the largest ship the Royal Navy has ever operated, is almost complete and the navy will also operate state-of-the-art Type 45 destroyers, new Type-26 Frigates, and seven new Astute Class submarines.”
And former Defence Secretary Liam Fox told the Today programme the Britain was “one of only four or five countries inside Nato” to meet the target of spending 2% of GDP on defence.
“America is the world's biggest economy with the world's biggest defence budget. We're the world's eighth biggest economy with the fourth biggest defence budget, so certainly we're pulling our weight on that,” he said.
The government's proposals to cut the number of regulars in the armed forces also include plans to increase the number of reservists.
But there have reports that army recruitment figures are below target.
Last week, Defence Secretary Philip Hammond said that while army recruitment represented a “big challenge” there was not a crisis.