Here are the top issues he'll be dealing with in his first trip to the region since March.
An increasingly urgent North Korea threat
Tillerson will be trying to twist arms in Manila to highlight the need for more pressure from countries that have ties to North Korea, first and foremost China.
It's unclear how differently this approach will be received than it was five months ago when Tillerson traveled to Japan, South Korea, and China -- a trip that ultimately failed to stop North Korea from its two ICBM tests.
The tactic of urging other countries to exert pressure is made even trickier by the presence of North Korea's foreign minister at the conference, although the U.S. delegation will do its best to isolate him and even push for North Korea's expulsion from the summit, the ASEAN Regional Forum, according to America's top diplomat for East Asia.
"What we would expect to see this year at the meeting would be a general chorus of condemnation of North Korea’s provocative behavior and pretty serious diplomatic isolation directed at the North Korean foreign minister," acting Assistant Secretary of State for East Asian and Pacific Affairs Susan Thornton told reporters Wednesday.
If anything, though, China has grown increasingly frustrated with the Trump administration, deflecting blame for the crisis to North Korea and the U.S.
"No matter how capable China is, China's efforts will not yield practical results because it depends on the two principal parties," Chinese ambassador to the U.N. Liu Jieyi said Monday.
With North Korea inching closer to having a nuclear-armed weapon, the question is whether time could be running out for Tillerson's diplomacy.
Face to face with Russia after new sanctions, diplomatic expulsions
Despite his push for better relations with Russia, Tillerson faced a huge setback in the last week with new congressional sanctions on Moscow and Russia's retaliation.
The secretary of state made his and Trump's distaste for the U.S. sanctions known, but now he has to enforce them and, in his view, soldier on to improve ties to Moscow despite them.
The first big step in that process is another face-to-face meeting with Russian Foreign Minister Sergei Lavrov. The two will meet on the sidelines of the summit after speaking on the phone Thursday -- their second call in a week.
"Our conversation following the actions has been professional. There's no -- there’s been no belligerence," Tillerson told reporters Tuesday, adding, "He’s as committed as I am to trying to find ways that we can bring this relationship back closer towards one another."
But critics question what the former ExxonMobil CEO could be willing to give to improve relations with Moscow and ultimately what he could potentially sacrifice for warmer relations with an adversary that continues to sow instability and confusion -- in Ukraine, Syria, eastern Europe, the American political system, and online.
With human rights not a top priority, will Tillerson meet with Philippines's strongman president?
The State Department has so far declined to say whom Tillerson will meet with from the Filipino government at the summit, and a question is whether he may dignify Duterte with a one-on-one meeting.
"We will be raising all of the relevant issues that we have in the bilateral alliance relationship with the Philippines," said Thornton, including "governance... and human rights issues."
But just how forcefully Tillerson will do that, especially as the U.S. fears Duterte's turn away from America and toward China, remains to be seen -- and however strongly, it will likely be only behind closed doors.
Is Trump's China honeymoon over?
At first, it seemed like the president who relentlessly bashed China on the campaign trail had found a close ally in China's President Xi Jinping. But after months of talks on trade, North Korea, the South China Sea, and more, relations between the world's two largest economies have started to fray.
Trump has begun lashing out on Twitter again against China for not doing enough to pressure North Korea. A Chinese state-run newspaper responded by criticizing the president's "emotional venting" on the social media platform.
Tillerson warned on Tuesday that renewed efforts are needed to avoid "open conflict," but within the administration, that dire warning is being met by possible new trade actions, specifically an investigation into Chinese theft of U.S. intellectual property.
Beijing, with an increasingly capable military and its strong economy, may respond just as assertively.
New terror hot spot?
En route to Manila during a stopover in Hawaii, Tillerson was briefed on the threat of ISIS and specifically the role of ISIS fighters returning to the Philippines from Syria by the commander of the U.S. Pacific Command, Adm. Harry Harris.
The Philippines has long struggled with Muslim separatists in the south, but now it is becoming ground zero for a growing new terror threat in Asia from Islamist jihadists.
The country's south, with a large Muslim population, has seen some violence from a surprisingly strong ISIS affiliate, which successfully captured the city of Marawi. The Filipino military has largely defeated the terror group, but a battle between the two sides still rages on.
There have also been attacks in Bangladesh and Indonesia, including by self-declared ISIS-linked groups, and there is a rising tide of conservative Islamism in political circles in some countries, including among the world's largest Muslim population in Indonesia.
That political ideology could become a breeding ground for violent jihadism, and part of Tillerson's mission is to work with regional allies to combat these trends.
"We are working together not just with the Philippines, but other countries in the region to try to address the growing concerns and growing threats, frankly, of international terrorism," Thornton said Wednesday.