Ms Okonjo-Iweala, 66, was named Director General by representatives of the 164 countries that make up the WTO, which deals with the rules of trade between nations based on negotiated agreements.
She said during an online news conference that she was taking over at a time when the WTO was "facing so many challenges".
"It's clear to me that deep and wide-ranging reforms are needed … it cannot be business as usual," she said.
Her first priority will be quickly addressing the economic and health consequences of the COVID-19 pandemic.
Strategies may include lifting export restrictions on supplies and vaccines, and encouraging the manufacturing of vaccines in more countries.
Other big tasks include reforming the organization’s dispute resolution process and finding ways for trade rules to deal with change like digitalization and e-commerce.
She takes over after four turbulent years in which former United States president Donald Trump used new tariffs, or import taxes, against China and the European Union to push his America-first trade agenda.
"It will not be easy because we also have the issue of lack of trust among members which has built up over time, not just among the US and China and the US and the EU … but also between developing and developed country members and we need to work through that," she said.
I absolutely do feel an additional burden, I can't lie about that ‑ being the first woman and the first African means that one really has to perform.
"All credit to members for electing me and making that history, but the bottom line is that if I want to really make Africa and women proud I have to produce results, and that's where my mind is at now."
The appointment, which takes effect on 1st March 2021, came after United States President Joe Biden endorsed her candidacy, which had been blocked by Trump.
Biden's move was a step toward his aim of supporting cooperative approaches to international problems after Trump's go-it-alone approach that launched multiple trade disputes.
But unblocking the appointment is only the start in dealing with US concerns about the WTO that date back to the Obama administration.
The US had blocked the appointment of new judges to the WTO's appellate body, essentially freezing its ability to resolve extended and complex trade disputes.
The US Government has argued the trade organization is slow-moving and bureaucratic, ill-equipped to handle problems posed by China's state-dominated economy, and unduly restrictive on US attempts to impose sanctions on countries that unfairly subsidies their companies or export at unusually low prices.
Chad P. Bown, senior fellow at the Peterson Institute for International Economics, said unblocking Ms Okonjo-Iweala's appointment was "a very good first step" in re-engaging with the WTO.
In particular, the WTO faces "a ticking time-bomb" in the form of other countries' challenges to Trump's use of national security as a justification for imposing tariffs, a little-used provision in US law rejected by key US trading partners in Europe.
Ms Okonjo-Iweala has been Nigeria's finance minister and, briefly, foreign minister, and had a 25-year career at the World Bank as an advocate for economic growth and development in poorer countries.
She rose to the number two position of Managing Director, where she oversaw US$104.1 billion in development finance in Africa, South and Central Asia, and Europe.
In 2012 she made an unsuccessful bid for the top post with the backing of African and other developing countries, challenging the traditional practice that the World Bank is always headed by an American.
She has a bachelor's degree in economics from Harvard University and a PhD in regional economics and development from the Massachusetts Institute of Technology.
South Korean Trade Minister Yoo Myung-hee withdrew her candidacy, leaving Ms Okonjo-Iweala as the only choice.
Her predecessor, Roberto Azevedo, stepped down on 31st August 2020, a year before his term expired.
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