One main boat carrying around 20 people accompanied by a group of smaller ones departed from the fishermen's port in Gaza City, AFP reported.
Salah Abd al-Ati, one of the organizers of the plan said the trip complies with all human rights regulations that ensure the right to travel and transportation.
“Gaza has become the largest isolated prison in the world and it does not receive its minimal rights because of Israel's blockade,” he added.
"We are sending a clear message to Israel and the rest of the world that the siege must be lifted," another organizers, Issam Hamad, said before the boats launched.
"Gazans are fed up with the lives they live."
Israel's blockade allows Palestinian vessels to travel nine nautical miles (16 kilometers) off the coast.
The Gaza Strip has been under an Israeli siege since June 2007. The blockade has caused a decline in the standards of living as well as unprecedented levels of unemployment and unrelenting poverty.
The Israeli regime denies about 1.8 million people in Gaza their basic rights, such as freedom of movement, jobs with proper wages as well as adequate health care and education.
The journey marks the anniversary of the May 2010 attack by Israeli commandos on an aid flotilla led by the Turkish ship Mavi Marmara. Nine people, eight of them Turks, were killed in the attack.
The development follows the six-week rallies at the Gaza fence. The protests have called for Palestinians who fled or were expelled in the 1948 war surrounding Israel's creation to be allowed to return to their former homes now inside Israel.
They peaked on May 14, when at least 61 Palestinians were killed as tens of thousands of Gazans protested and clashes erupted on the same day of the US transfer of its embassy in Israel from Tel Aviv to Al-Quds.
Demonstrations and clashes have continued at a low level since then. At least 121 Palestinians have been killed by Israeli fire and thousands more injured in the unrest.
Earlier Tuesday, Israel carried out strikes in the Gaza Strip after a barrage of mortar fire from the Palestinian enclave.
At least one base belonging to Hamas and four for Islamic Jihad, an allied group, were struck, Gazan security sources said. There were no immediate reports of injuries.
A Hamas spokesman confirmed only that "resistance" bases were being hit.
The firing of 28 mortar shells toward Israel caused no injuries, with most intercepted, but Prime Minister Benjamin Netanyahu vowed a forceful response.
It was the largest projectile barrage from Gaza targeting Israel since a 2014 war.
There was no immediate claim of responsibility for the mortars, but there was speculation they were fired by Islamic Jihad in revenge for a recent incident that left three of its members dead.
Hamas, the resistance movement that runs the Gaza Strip, said in a statement "what the resistance carried out this morning comes within the framework of the natural right to defend our people".
"The Israeli occupation bears full responsibility for any upcoming escalation."
AFP and Press TV contributed to this story.