The president is visiting the country of 1.1 million people in southern Africa to "celebrate the friendship between the two countries".
Ms Tsai will be in Eswatini, formerly known as Swaziland, from 5-7 September for the 55th anniversary of the country's independence, while marking 55 years of bilateral relations. She last visited the land-locked nation in 2018.
Calling Eswatini a "familiar old friend", Ms Tsai said, "Not only will Taiwan's footsteps to the world not stop, we will continue to move forward more firmly and self-confidently, so that the world can see Taiwan's steady force for good.”
Taiwan has provided large amounts of aid to the small southern African country ruled by an absolute monarchy, including in 2021 antiviral medication to help King Mswati III recover from Covid-19.
Accompanied by economy minister, Wang Mei-hua, the president will fly directly to the African nation without stopping anywhere, unlike her previous visit to Latin America which required transits via the US.
China claims Taiwan is obliged to reunite with the mainland, if necessary by force, despite the island being self-ruled since its split in 1949.
Beijing also frowns at Taiwan's diplomatic ties with foreign nations, which have reduced over the years with Taipei's once allies cowing to China's pressure.
Taiwan maintains official diplomatic relations with just 13 sovereign nations — almost all small less developed countries in Latin America, the Caribbean and the Pacific, like Belize and Nauru.
China has managed to poach nine countries since Ms Tsai took office in 2016, with Honduras being the latest to switch recognition to Beijing in March.
Beijing demands its allies agree to its One China principle, which claims that Taiwan is a part of the People's Republic of China.
"Diplomacy is the accumulation of step by step,” Ms Tsai said on Tuesday. Hinting at diplomatic expansion, she added that Taiwan’s “steps onto the globe” will not stop.
While the US does not officially recognises Taiwan as a sovereign nation, it maintains a robust relationship with the island. Earlier this month, Washington for the first time approved a direct transfer of $80m military aid to Taiwan under the Foreign Military Financing, which is a programme reserved for sovereign states.
However, Washington in a statement claimed the assistance does not imply any recognition of the sovereignty of Taiwan.
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