Saeed Jalili, deputy foreign minister for European and American affairs, was expected to replace Larijani, the official IRNA news agency said.
Larijani was set to meet EU foreign policy chief Javier Solana in Rome on Tuesday for more discussions about Iran's nuclear ambitions, which the West says are aimed at building atomic bombs despite Tehran's denials.
Government spokesman Gholamhossein Elham, quoted by IRNA, said Larijani's replacement was expected to meet Solana as planned.
Some analysts have said Larijani had differences with President Mahmoud Ahmadinejad over tactics in handling the atomic row. But the analysts have said both oppose halting the nuclear programme.
The final say in all matters of state, including nuclear policy, lies with Supreme Leader Ayatollah Ali Khamenei under Iran's system of clerical rule.
''Ali Larijani, the secretary of the Supreme National Security Council, resigned from his position,'' Elham said, adding that Ahmadinejad had accepted his resignation after previous offers by Larijani to resign were turned down.
''Despite Larijani's resignation, there will be no change in the council's programme and the new secretary will meet Javier Solana.'' REUTERS SZ BD1410