Mr Rodriguez said Cuba had lost some $96bn as a result of the embargo
Cuba has accused US President Barack Obama of not doing enough to end the US trade embargo against the island despite his promise to improve ties.
Earlier this week, Mr Obama renewed the embargo for another year.
In the first official Cuban reaction, Foreign Minister Bruno Rodriguez said the embargo was obsolete and unacceptable, and should be lifted.
His comments came as the two countries prepared to hold talks on resuming direct postal links.
On Monday, President Obama extended the US trade embargo on Cuba for another year, saying it was in the US national interest.
The trade ban would stay in place, Mr Obama said, until the communist government in Cuba freed political prisoners and improved human rights.
Reacting to the move on Wednesday, Mr Rodriguez said the embargo, which Cuba estimates has cost it $96bn since being imposed in 1962, should be ended without conditions.
"Obama was a president elected on a platform of change. Where are the changes in the blockade against Cuba," Mr Rodriguez told a news conference in Havana.
Mr Rodriguez said the US president was "well-intentioned and intelligent" and that the US had adopted a less aggressive tone towards Havana.
He said moves by the Obama administration to ease restrictions on Cuban-Americans who want to travel to Cuba or send money there were "positive" but had nothing to do with the embargo.
It was not up to Cuba to make concessions, he said. "The policy is unilateral and should be lifted unilaterally."
Mr Rodriguez renewed an offer to hold direct talks with President Obama, but Cuba "would not discuss its internal affairs with with anyone, not with the US nor with any group of countries".
On Thursday, US and Cuban delegations are due to meet in Havana about the possible resumption of direct postal services between the two nations.
"These are really exploratory talks and they are very technical in nature...We see it as a potential avenue for improving direct communication between our two countries," state department spokesman Ian Kelly said.
Direct services were suspended in 1963 and currently post must go through third countries, meaning it can take several weeks to arrive.