The combination left investors scurrying for safety as global equities took a knock, the dollar fell and bonds rose.
MSCI's broadest index of Asia-Pacific shares outside Japan fell 0.3 per cent, retreating from a one-and-a-half month high hit on Tuesday.
Australian shares stumbled 0.8 per cent in early trade, while Japan's Nikkei dropped 0.8 per cent. South Korea's Kospi index declined 0.7 per cent.
The weakness followed losses on Wall Street, with the Dow off 0.7 per cent, the S&P 500 down 0.6 per cent and the Nasdaq Composite down 1.0 per cent.
Mr Trump fired Secretary of State Rex Tillerson on Tuesday after a series of public rifts over policy on North Korea, Russia and Iran, replacing his chief diplomat with hawkish CIA Director Mike Pompeo.
Critics said the move would sow more instability in the volatile Trump administration and marks the departure of another moderate who sought to emphasize the United States' strong ties to its allies.
Separately, Mr Trump is also looking to impose tariffs on up to $60 billion of Chinese imports, targeted at information technology, consumer electronics and telecoms, two people who had discussed the issue with the Trump administration said.
"Tillerson's departure has left some worrying that it provides a green light to those in the office pushing for more protectionist measures," analysts at ANZ Bank said in a note to clients. "Protectionism is on the rise."
Investors suspect policy makers who favour protectionism will also seek to use the currency as a trade weapon, if not overtly then through benign neglect.
Mr Tillerson's exit and the potential for new import duties on China coincided with subdued US consumer price data with annual core inflation, at 1.8 per cent, meeting expectations.
The euro rose overnight to edge towards a recent one-month top of $1.2446 . It was last at $1.2393.
"Many traders feel that equities could have ended higher if it weren't for 'Rexit'," analysts at Citi said referring to Mr Tillerson's departure.
It was the fear of higher inflation and in-turn faster US rate hikes that had hit global shares in early February. But Tuesday's data did little to change market expectations of Fed rate rises with an increase next week now fully priced in.
"While Tillerson's exit has been rumoured for months, it speaks to persistent Trump turnover and potentially, more market-alarming, protectionist headlines," Citi analysts added.
Since Mr Trump took office in 2017 as many as 35 senior officials from his administration have walked out, including Mr Tillerson, according to Citi.
In commodities, oil prices inched up after two straight days of losses after data showed a smaller-than-expected build in crude inventories.
US crude rose 18 cents to $60.89.
Spot gold was steady at $1,326 an ounce.
(This story has not been edited by NDTV staff and is auto-generated from a syndicated feed.)