Macau, a former Portuguese colony-turned-special administrative region under China's "one country, two systems" framework, will hold an election on October 13 in which only around 400 pro-establishment figures are allowed to vote.
Incumbent leader Ho Iat-seng announced last week his plans to step down in December, citing health concerns.
Sam, who had resigned from his position as president of Macau's highest court the day before, said Wednesday in a press conference that he has "decided to run for the office of the sixth chief executive of the Macau Special Administrative Region".
No other candidates have declared a bid, and the nomination period runs from Thursday to September 12. Any new leader would need approval from Beijing's central government.
If elected, 62-year-old Sam would become the first Macau leader with a legal background, in contrast to his three predecessors who all hailed from the business sector.
The city's fortunes have long been pegged to its booming casino industry, though Chinese leader Xi Jinping has urged Macau to diversify its economy.
Sam said Wednesday the city's economic and political development faced "unavoidable" challenges, and that Macau needed to "reform and innovate".
"Macau's long-term development is only possible with the country's support," Sam said, stressing the need to serve China's development blueprint.
"Macau must take timely measures to integrate in order to seize these opportunities, otherwise we will gradually fall behind."
Born in Zhongshan, a mainland Chinese city, in 1962, Sam would be the first leader not born in Macau if he is elected.
He graduated from the elite law school of China's Peking University and received further education in Portugal.
Sam was among the first batch of judges trained in Macau's Magistrates Training Centre and was appointed the president of Macau's Court of Final Appeal on the same day the territory was handed back to China on December 20, 1999.
Under Sam's leadership, Macau's apex court in 2021 outlawed the peaceful candlelight vigil held to commemorate the 1989 Tiananmen Square crackdown.
The same year, Sam and his fellow judges ruled in favour of the Macau government's decision to bar 21 pro-democracy candidates from running for the city's legislature.
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