Tánaiste Simon Coveney has called for an independent investigation into what he says seems to be a "disproportionate" use of force by the Israeli defence forces.
The latest death toll stands at 52 after Israeli soldiers shot and killed Palestinians during mass protests along the Gaza border, overshadowing the inauguration of the new US embassy in Jerusalem.
According to Gaza health officials, more than 1,200 people have also been wounded.
In a show of anger fuelled by the embassy move, protesters set tyres ablaze and hurled firebombs and stones toward Israeli troops across the border.
The Israeli military said its troops had come under fire, and accused protesters of trying to break through the border fence. It said troops shot and killed three Palestinians who were trying to plant a bomb.
Minister for Foreign Affairs Coveney expressed his "profound shock" at the deaths and called for the Israeli army to show restraint to avoid a higher death toll.
"I am gravely concerned that the use of force seems disproportionate to the reported threat, and I reiterate that an independent investigation is urgently needed, as called for by the UN Secretary-General," said Mr Coveney.
"It is essential that Israeli forces show restraint, if this tragic death toll is not to climb even higher. In the context of the opening of the US Embassy in Jerusalem, I call on all leaders to ensure that their statements today promote calm and do not further inflame tensions."
In a tweet from Washington, US President Donald Trump did not refer to the violence, declaring it: "A great day for Israel!"