Tipped as a rising star within Labour and a possible future leader, Purnell is the fifth minister to quit in recent days -- the third at Cabinet level -- piling the pressure on Brown.
However, while the others were under fire in the MPs' expenses row, Purnell was not and was the first government member to quit while calling openly for Brown's resignation.
Purnell left as the polls closed Thursday, with all eyes on whether other ministers would follow suit and turn against Brown.
Brown now faces a difficult Cabinet reshuffle, which could take place later Friday if he decides not to hold off until Monday when the election results will be known.
While some senior figures like deputy Labour leader Harriet Harman have backed Brown in the wake of Purnell's departure, others may turn against him if he tries to demote them in the reshuffle.
"I now believe that your continued leadership makes a Conservative victory more, not less, likely. That would be disastrous for our country," Purnell wrote in a letter published in The Times and The Sun.
"I am therefore calling on you to stand aside to give our party a fighting chance of winning. As such I am resigning from government.
"I am not seeking the leadership nor acting with anyone else. My actions are my own considered view, and nothing more."
Brown was left "disappointed" by Purnell's departure and was now concentrating on "restructuring the government", a spokesman for his Downing Street office said.
Conservatives leader David Cameron said Purnell's departure showed that the government was "falling apart in front of our eyes" and urged an immediate general election. Brown has until May 2010 to call one.
Communities Secretary Hazel Blears, who faced criticism over her expenses, resigned on Wednesday, while Home Secretary Jacqui Smith said she would step down at the reshuffle, which could happen Friday if Brown decides to act before leaving for the D-Day commemorations in France this weekend.
In power since 1997, Labour has borne the brunt of public outrage over lawmakers' dodgy expenses claims, a row made worse by the fact Britain is struggling to climb out of its worst recession in decades.
Speculation that Brown was preparing to step down -- dismissed as "complete nonsense" by his spokesman -- sent the pound crashing against the euro and dollar on Thursday.
Chancellor of the Exchequer for 10 years, Brown took over from Tony Blair as Labour leader and prime minister in June 2007.
Labour's rules make it tough to evict a sitting prime minister, though the party's MPs could make Brown's position untenable through withdrawing their support.
The first local election results were out early Friday, with Labour losing councillors to the Conservatives and Liberal Democrats' gain.
The European poll results are being held back till Sunday, in line with other EU countries.
Britain's 72 seats in the European Parliament were up for grabs, while voters in various parts of England also chose 2,318 local councillors and three mayors.
Opinion polls suggested Labour could finish behind the Conservatives, the Liberal Democrats, and even fringe eurosceptics the United Kingdom Independence Party.
Source: AFP European Edition