The Wolf of Wall Street star has been criticised over his rumoured romance with 19-year-old model Eden Polani who is 29 years younger than the actor.
After posting a number of tweets about the Oscar winner, one Twitter user asked Ryan what crime DiCaprio had committed to which she replied: "No crime just a creepy pattern."
Ryan also also wrote "uh huh" in response to a separate tweet which read: "The power dynamic of his age, his wealth, and his fame over a 19 year old girl is actually repulsive."
The comedian went on to joke: "This year, Titanic became too old for Leonardo DiCaprio to be in it."
DiCaprio has recently been criticised over his penchant for dating women under the age of 25 with the exception of model Gigi Hadid, who would be the only person he has been in a public relationship older than that.
Ryan has recently been vocal about abuse in the entertainment industry and claims she confronted a well known entertainer on a panel show about their behaviour.
In an interview with Louis Theroux, Ryan said: "I’m happy to have it, but it’s a litigious minefield because lots of people have tried to nail this person down for their alleged crimes and this person has very good lawyers, so am I going to put my mortgage on the line by saying who this person is or entering into any conversations like that?"
She added: "It’s not really my story to tell. No one has perpetrated any sexual assault against me, but this person, I believe very strongly – many people believe very strongly – is an open secret, is a perpetrator of sexual assault."
Ryan also confirmed that the remarks she made on the panel show were cut from the final broadcast.
Watch below: Dame Joanna Lumley says Leonardo DiCaprio is 'just golden'