The United States and Saudi Arabia have a decades-old relationship based on the exchange of American security for Saudi oil.
But ties between Riyadh and Washington became increasingly frayed during the administration of president Barack Obama.
Saudi leaders felt Obama was reluctant to get involved in the civil war in Syria and was tilting toward Riyadh's regional rival Iran.
The Sunni Muslim kingdom "felt marginalised" during international negotiations on a nuclear accord with Shiite Iran, an American defence official said.
That deal, signed in July 2015 by the Obama administration, saw the lifting of international sanctions in exchange for guarantees that Tehran will not pursue a nuclear weapons capability.
Mattis arrived in Riyadh Tuesday afternoon, wishing to "reinvigorate" ties by listening to Saudi leaders and learning "what are their priorities", the official said.
The retired four-star Marine general will meet King Salman, Crown Prince Mohammed bin Nayef, and Salman's son Deputy Crown Prince Mohammed bin Salman, who holds the defence portfolio.
The deputy crown prince last month met President Donald Trump in Washington.
Saudi leaders worry about Iran interfering in Arab countries by using Shiite communities to advance their pawns, as in Bahrain, Lebanon and Yemen.
- New Iran sanctions -
Bordering Saudi Arabia, Yemen has been torn for more than two years by a civil war between Iran-backed Huthi rebels, their allies, and pro-government forces aided by a Saudi-led military coalition that receives some military support from the US.
The Saudis have found a more favourable ear in Washington under Trump, who denounces Iran's "harmful influence" in the Middle East.
Mattis has called Iran "the single biggest state sponsor of terrorism in the world".
In February, Trump imposed new sanctions on Tehran after a ballistic missile test launch, and in response to its support for Yemen's rebels.
The US military is watching Huthi activities along the strategic Bab al-Mandab strait connecting the Red Sea with the Indian Ocean.
Rebels in late January attacked a Saudi warship in the Red Sea, and they are also believed to have fired missiles towards US warships in the area.
The United States accuses the rebels of deploying coastal defence missiles and other weapons which threaten free navigation in the waterway which is vital to global trade.
"I am extraordinarily concerned about another contested maritime chokepoint in the region," US Central Command chief General Joseph Votel told the House Armed Services Committee in March.
Tensions with Iran were already high over another waterway, the Strait of Hormuz which links the Gulf and the Indian Ocean.
Iran aims to become the "predominant power" in the Middle East, Votel said.
- Anti-IS campaign -
Trump's Yemen focus has so far been on a major escalation of attacks against jihadists from the Al-Qaeda in the Arabian Peninsula group in Yemen.
Pentagon officials have so far remained cautious on what they might do to support Saudi Arabia.
The Trump administration could, for example, lift a freeze on the delivery of precision guided bombs to the kingdom.
Obama's government blocked their transfer in December because of concerns over civilian casualties in Yemen.
Trump could also decide to reinforce support for the Arab coalition in Yemen, even if his administration wants the return "as quickly as possible" of UN-backed peace talks, as Mattis said at the start of his Saudi trip.
Washington would also like Riyadh to step up its participation in the campaign against the Islamic State group in Iraq and Syria.
Options include the kingdom intensifying its aerial operations or its humanitarian aid, the American defence official said, describing the fight against IS as "our number one concern".
Mattis is expected to evoke with the Saudis Washington's intentions towards Syria, where Riyadh has aided some rebel groups.
For the first time in six years of Syria's war, the American military intervened directly against the regime of Bashar al-Assad by firing 59 cruise missiles at a Syrian government airbase.
Saudi Arabia applauded this month's strike after a suspected chemical bombing of a rebel-held town which the US blamed on Assad.
After Saudi Arabia, Mattis travels Thursday to Egypt and then to Israel on Friday before returning to the Gulf Saturday for talks in Qatar.
Some conservative American analysts say the US should build a common front between Israel and the Gulf monarchies, who have no diplomatic relations with the Jewish state.