Clooney joined the president of Armenia Serzh Sargsyan in the solemn ceremony a day after the actor called for the events of 1915 to be recognised internationally as genocide.
Armenians say the Ottoman Empire killed 1.5m of its people, beginning on April 24, 1915.
Modern-day Turkey strongly disputes claims that the events were a genocide, and the figures stated.
Clooney, who is visiting Armenia for the first time, later handed out a €900,000 award as part of the Aurora Prize humanitarian event held to recognise those who put themselves at risk to save the lives of others.
During the 20-minute ceremony Clooney took part in a procession with Armenian politicians and military, before laying a flower at the memorial and soberly standing alongside Sargsyan.
Flanked by two security guards, Clooney, dressed in a dark suit and black tie, wore the Armenian remembrance brooch — a purple forget-me-not flower — on his jacket.
During his visit to the country’s capital, the Oscar-winning actor called for the events of 1915 to be recognised internationally as genocide.
He said: “When someone is trying to annihilate a whole human race, culture, people, that’s genocide, there can be no other version of it.”
Just a handful of countries officially recognise the Armenian genocide, including France and Russia. At the time Britain condemned the actions of the Ottoman Empire, but has never officially recognised the event as a genocide.
On Saturday, thousands of demonstrators demanding recognition from Turkey and the international community marched to the memorial in Yerevan. A small crowd was seen burning Turkish and Azerbaijani flags.
Armenia has a fraught relationship with Azerbaijan over the conflicted Nagorno-Karabakh region, where around 75 soldiers were killed earlier this month after an outbreak of fighting.
Clooney also spoke out about how he combats the “suffocation” caused by his fame to focus the attention on those “who couldn’t get any cameras on them”.
He said he felt “lucky” to be born in the US and “not born as a young woman who was taken by Boko Haram.”