The sub went missing in the Atlantic on an underwater journey to the wreck of the Titanic, with five people on board.
A large search is under way, with experts predicting that the vessel will soon run out of oxygen.
Commenting on the search on Twitter, Cusack appeared to reference the migrant boat that recently sank off Greece, leaving 78 dead and hundreds missing.
“All I can think is refugees capsize no one cares – some billionaires on joy rides go missing – it seems like multiple navy’s are instantly searching,” the 56-year-old posted.
Many people chimed in to agree with the actor, who is known for films such as Sixteen Candles and Being John Malkovich.
One person tweeted that it was “infuriating” and another said: “It’s really, really sad when it’s right in front you. Money people mean more than anyone else.”
“I just got done saying the same thing…” said one fan.
“Five billionaires get lost in a s****** submersible on a $250k per person trip to see the Titanic, and half the US Coast Guard gets mobilised to find them.
“Innocent refugees get lost at sea trying to make their way to safety and a better life, and no one can be bothered to give a crap.”
However, another said: “I agree that society is very one-sided but in my mind they’re still people.”
“We have to watch the way we refer to people with money,” said someone else.
“It is not fair to think they are less than just because they are rich.”
One fan suggested people have been gripped by the story because “we can see ourselves in a tourist junket that goes awry”.
“Plausible something like that could happen to us,” they said.
“We don’t really see ourselves in a boat full of other refugees.
“I think people are by and large only empathetic to those with whom they can identify.”