Obama spoke during a visit originally planned as a valedictory lap, but which has become focused on reassuring jittery allies after the shock election victory by Donald Trump, a staunch critic of free trade agreements.
"The global path of globalisation demands a course correction," Obama said in an eagerly-awaited speech in Athens, before continuing his journey to Berlin.
"When we see people, global elites, wealthy corporations seemingly living by a different set of rules, avoiding taxes, manipulating loopholes... This feeds a profound sense of injustice," he added.
In comments yesterday, Obama cautioned the world must guard against "a rise in a crude sort of nationalism or ethnic identity or tribalism that is built around an 'us' and a 'them'".
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European governments, especially eastern countries close to Russia's orbit, have been shaken after Trump appeared to call into question Washington's near 70-year security guarantee by saying he would only help NATO allies if they paid their way.
However, Obama was at pains to stress that Europe - and NATO - would remain the cornerstone of US foreign policy.
The US-led NATO grouping is "absolutely vital" to US interests and a strong, unified Europe was good for America and the world, Obama said in comments aimed at reassuring old partners.
"We know what happens when Europeans start dividing themselves up... The 20th century was a bloodbath," he said pointedly yesterday.
Following his speech, the president will head to Germany to visit Chancellor Angela Merkel, whom he has described as "probably... My closest international partner these last eight years."
While Obama has generally been welcomed in Greece, there were some who came out onto the streets in protest.