Half of the refugee camp -- one of the largest in Greece -- was destroyed by the fire, which police and witnesses say was started by some of the people who lived there.
Earlier in the day, around 2,000 refugees staged a protest, calling on authorities to speed up the asylum application process, according to independent volunteer Ihab Abassi, who was on the grounds at the time.
Fighting erupted between some refugees during the rally and some set fire to the site, authorities said. Lesbos police reported nine people were arrested.
"Over 50 UNHCR Refugee Housing Units, accommodating some 800 people, were completely destroyed," United Nations Refugee Agency spokesman William Spindler said in a statement.
Thirty people were taken to hospitals with "light injuries," he added.
The UNHCR has provided replacement tents for refugees left homeless by the blaze.
Frustrations flow over
The island of Lesbos currently hosts more than 5,300 refugees -- yet has a capacity of just 3,500, said Spindler.
"Poor living conditions, combined with a prevailing feeling of uncertainty, regularly fuel despair and frustration among asylum-seekers in Greece," he added.
The UNHCR urged authorities to speed up the transfer of unaccompanied children to the mainland, and introduce shorter waiting times for asylum claims.
Lesbos: Gateway to Europe
For the hundreds of thousands of migrants fleeing war in the Middle East and making the treacherous sea crossing to Greece, Lesbos is often their first stop.
This year, 264,513 people arrived in Europe by sea,
landing mostly in Greece and Italy, according to International Organization of Migration (IOM) estimates released in mid-August.
Of those who attempted the crossing, 3,165 people have died at sea, authorities said. At this rate, according to the IOM, the number of deaths will likely exceed last year's total of 3,771.