The Redzikowo base, 230 kilometres (143 miles) from the Russian border, has been operational since July but was officially inaugurated only on Wednesday.
"A US destroyer on Polish soil has become a fact," Polish Defence Minister Wladyslaw Kosiniak-Kamysz said at the ribbon-cutting ceremony, describing it as "of historical importance for the security of Poland, the United States and NATO".
"Through the conflicts which are ongoing right now, the conflict in Ukraine or in the Middle East, we can see how important air defence and missile defence is," he added.
First announced in 2009, the project was plagued by delays, and Russia has since emerged as the main security concern for the military alliance's eastern flank.
NATO chief Mark Rutte told reporters in Warsaw the base "significantly enhances our ability to defend against the growing threat of ballistic missiles from outside the Euro-Atlantic area".
Despite NATO stating that the Redzikowo facility and a similar system in Romania are purely defensive, Moscow has frequently labelled it a threat.
The new base "constitutes an advance of US military infrastructure in Europe towards our borders", Kremlin spokesman Dmitry Peskov told reporters Wednesday.
The inauguration comes as Warsaw and its regional allies brace for the US presidency of Donald Trump, who in the past has voiced admiration for Russian President Vladimir Putin.
But US Ambassador Mark Brzezinski said at the ceremony he was "confident that this close partnership between our two nations will continue".
On Tuesday, Foreign Minister Radoslaw Sikorski welcomed the project in a post on social media as "proof of the geostrategic consistency of the United States".
- 'Ever more aggressive' enemies -
The base is part of a broader NATO missile shield -- dubbed "Aegis Ashore" -- which includes a system of radars that could intercept short- and medium-range ballistic missiles.
Admiral Stuart Munsch, commander of the US naval forces in Europe and Africa, said "building our defences now is vitally important".
"Global adversaries are becoming ever more aggressive, challenging the international order," he said at the ceremony.
"While the threat of ballistic missiles is concerning, the technology and the highly skilled operators of this Aegis Ashore site give us confidence in our defence."
Polish general Mieczyslaw Bieniek, a former high-ranking NATO official, told the Polish news agency PAP there was potential to further develop the base's capabilities.
"There is technological possibility for this system to also be equipped with missiles of a different type that could counter cruise missiles, which would further reinforce our security," he said.
But defence expert Marek Swierczynski questioned "to what extent the base or the anti-missile system was adapted to the threat of Russia and Belarus".
He said that the initial conception of the long-delayed project was to counter "threats mainly from Iran".
"This base is in a way a relic, a remnant of a previous system of thinking about European security which is not very compatible with the threat represented by Russia for example," he told AFP.
NATO chief Rutte called the base's opening "an important milestone" but said the alliance would work towards "the full development of a NATO ballistic missile defence".
"NATO must have the means to address threats from any direction... So we will work on this, step by step," he told reporters after talks with Polish President Andrzej Duda in Warsaw late Wednesday.
More than 10,000 US troops are currently stationed in Poland, one of the staunchest supporters of neighbouring Ukraine, which is struggling to fend off a Russian invasion since 2022.
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