Leading Conservatives say the former deputy Labour leader's move – as well as ex-MP Ian Austin's endorsement of Boris Johnson – showed that Labour had been "completely taken over" by the hard-left.
Mr Watson, who has repeatedly clashed with Jeremy Corbyn, insists his decision to quit was "personal not political", while Mr Austin said the Labour leader was "unfit to lead the country".
Speaking during a visit to Dudley, Tory party chairman James Cleverly described Mr Austin as "an honourable guy".
"I don't agree with him politically, but the fact that a lifelong Labour guy is basically saying that the leader of the Labour Party is completely and in every respect unsuitable to be Prime Minister, people have got to listen to that.
"With Tom Watson standing down, it is now clear that the hard left have completely taken over the Labour Party. He is basically admitted that fight for the soul of the Labour Party is lost."
South Staffordshire MP and Education Secretary Gavin Williamson, who was brought up in a labour supporting family, has also had his say.
He told the Express & Star that Mr Watson and Mr Austin were both "steeped in the Labour Party's history" and had done "so much for the party".
"To see the Labour Party is no longer really a home for them or that they don't want to be a part of it actually goes to say an awful lot," he said.
"The fact that Ian is saying you have got to be backing the Conservatives is an incredibly powerful message and one I hope a lot of people will listen to.
"The Labour Party that my family, my parents, my grandparents always supported, that's not the Labour Party of Jeremy Corbyn.
"Jeremy Corbyn is a very different type of Labour politician and that's what you're seeing with Ian Austin leaving and saying people should be voting Conservative."
On Mr Watson, he added: "I am deeply saddened to see him go. As someone who served as an MP alongside Tom, I know how committed he was to his constituency to the region and also to the Labour Party."
West Midlands Mayor Andy Street, said of Mr Austin's move: "I understand how hard this must have been for him and I respect him for it.
"Ian you have always acted with great dignity and I wish you well for your future."
Chancellor Sajid Javid said Mr Austin was "a brave man", adding: "Ian is Labour to his core, but knows that Jeremy Corbyn is completely unfit to lead."
Meanwhile Labour's Diane Abbott has been criticised over a tweet which appeared to suggest Mr Austin's comments had been given favourable media coverage.
The shadow home secretary's tweet, which was shared by Wolverhampton South West's Labour candidate Eleanor Smith, said: "Ian Austin, one year as a junior minister at DCLG, says he won't vote for Labour. Wall-to-wall coverage.
"Ken Clarke, nine years as Secretary of State, including as Chancellor, says he won't vote for the Conservatives. Silence.
"Balanced election coverage?"
Mike Wood, the Tory parliamentary candidate for Dudley South, said: "At no point has Ken Clarke said Boris Johnson is completely unfit to be Prime Minister, and he has certainly not advised people to vote Labour.
"There is no comparison. What this shows is that Diane Abbott does not understand the serious and fundamental problems that the Labour Party has.
"She reinforces everything Ian has said."
Mr Austin this afternoon hit back at claims from shadow chancellor John McDonnell that he was "employed by the Tories".
Describing the comment as "a complete lie", Mr Austin said: "I was appointed an unpaid trade envoy in July, along with 27 other MPs and peers from different parties, including Labour, to promote UK trade and exports.
"John should withdraw this lie and apologise."