Following these setbacks, the group "needed to somehow regain the initiative," Wainwright said in a recent interview. "We're starting to see [it is] like an animal caged in the corner [that's starting] to sort of lash out, and I think it might be part of the slow, long decline of the organization."
"I think we're seeing the biggest threat for a generation," the Welsh-born official said. "In terms of the numbers of radicalized people, in terms of the acts of terrorism, the brutal acts that we've seen on the streets of Europe, I haven't seen anything like it for some time."
He has "no doubt" that Euro 2016 will be on the target list, noting that ISIS "has a taste for the spectacular."
One of the shooters who killed 14 people in San Bernardino, California, in December pledged allegiance to ISIS, according to law enforcement sources, but the extremist group stopped short of taking credit for the attack.
Wainwright said ISIS would like to target the U.S. but is hindered by geography, border security and a smaller pool of foreign fighters than Europe.
Nevertheless he said the U.S. was "not complacent" and added that there were 20 U.S. federal agents working at Europol as part of a wider collaboration with Washington.
The short-term focus is on Euro 2016, which started Friday and is being policed by some of the strictest security ever seen at an event its size.
"When we're faced with such a complex threat we cannot reduce it to zero," he said of the chance of an attack. "There can't be totally security in society unless we give up some of the freedoms and the values that we cherish in Western democracies, and of course we're not prepared to do that because that would bending in the face of terrorism."
Europol works with the E.U.'s 28 member states, as well as other countries such as the United States, to help information sharing and cooperation.
Despite these efforts, Wainwright admitted that countries had only a "fragmented intelligence picture" of the estimated 5,000 so-called foreign fighters who have fled Europe to join ISIS.
In the era of 9/11 and al Qaeda, many recruits would be radicalized over a number of months or years by attending extremist sermons, but now young people were being radicalized online "very, very quickly," according to the police director.
Despite all this, he was adamant: "I've no doubt we will succeed, in the end, in defeating ISIS."
Bill Neely is NBC News' chief global correspondent. He joined NBC News from Britain’s ITV News in January 2014. His reports from across the globe have earned many awards, including an unprecedented three consecutive BAFTAs, the British equivalent of the Oscars, for his work in China, Haiti, and the U.K.
Michele Neubert is a London-based producer for NBC News. She has been awarded four Emmys, an Ed Murrow and Dupont Award for her work in conflict zones, including the Balkans, Afghanistan and Kurdistan.
Alexander Smith is a senior reporter for NBC News Digital based in London.