It will be the third meeting of the two leaders in Paris since last July, and while they agree on the threats posed by Tehran's missile projects and foreign interventions, they differ strongly on the response.
Netanyahu has pursued his strident attacks against Tehran during his visit to Europe, warning during a stop in Berlin on Monday that its activities risked fuelling a new influx of migrants towards Germany.
Iran was intent on fuelling "a religious war inside Syria and the consequences will be many, many more refugees and you know where exactly they will come," he told German Chancellor Angela Merkel.
Netanyahu has been emboldened by US President Donald Trump's decision to pull out of the 2015 accord curbing Iran's nuclear programme and the threat of harsh sanctions against European firms doing business in the country.
Yet Macron has led a staunch defence of the accord, whose other signatories -- France, Britain, Germany, China, Russia and the EU -- have maintained a common front so far.
"Benjamin Netanyahu's goal is to not find himself isolated along with Washington," said David Khalfa of the Institute for European Prospective and Security in Paris.
"At a minimum he's looking to force Europeans to reinforce the existing accord" via the US sanctions, but also the prospect of joint Saudi-US-Israel bloc setting the agenda in the Middle East, Khalfa said.
Macron has warned that letting the deal fall apart will only inflame tensions, especially if harsh sanctions smother the economic relief Iranians began to enjoy after it was signed in 2015.
He and Netanyahu are scheduled to hold a press conference after their talks and launch a season of cultural exchanges between their countries this year.
But relations have been further strained by the killing of 123 Palestinian protesters in Gaza by Israeli forces since March, including at least 61 people on May 14 alone.
Macron denounced the "violence by Israel's armed forces" even as he noted the country's security concerns, a position deemed too simplistic by Israeli officials while also being derided by his leftwing critics in France.
French Prime Minister Edouard Philippe cancelled a planned trip to Israel last month.
Several pro-Palestinian groups are planning protests against Netanyahu in cities across the country, while three journalist unions have called his visit "intolerable".
The journalist unions denounced the killing of Palestinian journalists by Israeli forces, as well as women, children and people working for emergency services in Gaza.
Against this backdrop, talks on seeking an end to the Palestinian conflict have fallen to the wayside, not least after Trump broke with decades of protocol by recognising Israel's claim of Jerusalem as its capital.
Last week, the European Union urged Israel to reconsider its decision to demolish a Palestinian Bedouin village in the occupied West Bank, saying it undermines "prospects for a lasting peace".
Macron has announced plans to visit both Israel and the Palestinian territories this year.
"Macron is taking a very pragmatic approach, separating the Israeli-Palestinian conflict from their bilateral cooperation," said Khalfa, noting in particular Macron's appreciation of Israel's push to become a "start-up nation".
Macron and Netanyahu are also planning to inaugurate a show highlighting Israel's technological innovations, "Israel@lights", at the Grand Palais museum in Paris.