Wang hit out at what he called efforts by Washington "to suppress China", telling reporters that "the desire to heap blame under any pretext has reached an unbelievable level".
Beijing's top diplomat met the press Thursday on the sidelines of China's largest annual political gathering, which opened in the capital earlier this week.
The "Two Sessions" -- parallel meetings of China's rubber-stamp parliament and political consultative body -- offer a rare glimpse into the strategy of President Xi Jinping's Communist Party-led government for the year ahead.
This year's gathering is being closely watched for signals as to Chinese leaders' confidence in current geopolitical conditions, as tensions persist across the Taiwan Strait and Russia's war in Ukraine enters its third year.
China's expanding political reach has sparked friction on multiple fronts, with Wang's press conference coming after Southeast Asian and Australian leaders warned this week against Chinese actions that "endanger peace" in the South China Sea.
Beijing has increasingly flexed its muscles in the South China Sea, which it claims in almost its entirety despite an international arbitration ruling that declared its stance baseless.
Chinese coast guard boats were accused on Tuesday of badgering a flotilla of Philippine ships on a resupply mission, with Beijing in turn saying Manila was acting as Washington's pawn.
"We resolutely oppose all acts of hegemony and bullying, and will strongly uphold national sovereignty and security as well as development interests," Wang said Thursday.
"The methods used to suppress China are constantly being renewed, and the list of unilateral sanctions is constantly being extended," he said at a press conference in Beijing, referring to US actions.
And the veteran diplomat warned that people seeking independence for self-ruled Taiwan, which Beijing claims as its territory, would be "liquidated by history".
- Maritime tensions -
Wang insisted on Thursday that China's actions in the South China Sea were reasonable, saying Beijing had "always maintained a high degree of restraint".
Manila has accused China of harassing Philippine vessels in the contested waters, including blasting a resupply boat with a water cannon on Tuesday.
Philippine President Ferdinand Marcos said he viewed the Chinese actions with "great alarm", while a Filipino military commander described the confrontations as "the worst" in two years.
Wang told journalists that Beijing "advocates the spirit of essential good-neighbourliness... but we will not allow goodwill to be abused".
"We will legitimately defend our rights in accordance with the law," he said, urging "certain countries outside the region not to stir up trouble or pick sides, and not to become disruptors or troublemakers in the South China Sea".
"In the face of complex turmoil in the international environment, China will persist in being a force for peace, a force for stability, and a force for progress in the world," Wang told reporters.
- 'New paradigm' -
Wang reiterated China's support for Palestinians when asked about the ongoing conflict in Gaza, saying Beijing supports full United Nations membership for a Palestinian state.
"The catastrophe in Gaza once again reminded the world that the fact that the Palestinian territories have been occupied for a long time can no longer be ignored," Wang said.
"The long-cherished wish of the Palestinian people to establish an independent country can no longer be evaded, and the historical injustice suffered by the Palestinian people cannot continue for generations without being corrected," he added.
He called the conflict "a tragedy for humankind and a disgrace for civilisation".
Beijing has been calling for an immediate ceasefire since the start of the current Israel-Hamas war in October last year.
Wang on Thursday also defended Beijing's close relationship with Moscow, saying that "China and Russia have set a new paradigm for major power relations that is completely different from the old Cold War era."
The foreign minister said that bilateral ties rested on "the basis of non-alignment, non-confrontation and non-targeting of third parties".
Western powers have criticised Beijing for refusing to condemn Moscow for its invasion of Ukraine in February 2022.
China says it is a neutral party in the Ukraine war, but its strategic partnership with Russia has grown closer since the start of the war.
Wang also told reporters on Thursday that the European Union's portrayal of China as a rival was "not factual or feasible", amid efforts by the bloc to fend off competition from China in areas including technology, energy and electric vehicles.
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