Olli Rehn and Manuel Barroso threw their weight behind Mr Letta who also appealed for stability before a Senate vote on Wednesday on whether Silvio Berlusconi should be expelled from parliament following a conviction for tax fraud.
Mr Rehn, the EU's top economic official, said: "I believe it is of paramount importance to keep political stability in the country to ensure a recovery, mainly because the latest data show the economy remains relativity weak, without clearly indicating a return to growth."
Political instability has thwarted attempts to make the economy more competitive and whittle down Italy's government debt burden, one of the world's biggest.
Berlusconi's centre-right allies have threatened to sink the government if Wednesday's vote goes against him.
Mr Letta's left-right coalition, which needs the backing of Berlusconi's People of Freedom party to survive, has bickered since it was formed in April but the infighting has intensified since Berlusconi was sentenced last month.
Mr Barroso, the president of the European Commission, said it was his duty to demand a greater sense of responsibility from all political forces.
He added: "Italy needs systemic stability. It's one of the big countries of the euro zone: when signs of political instability emerge there are repercussions on the markets."
Mr Letta also made an impassioned appeal for political stability, warning a political crisis would push up borrowing costs and throw Italy into chaos.