Taoiseach Varadkar was filming in Merrion Square on Friday afternoon when the woman, who was wearing a mask, threw a drink at him and then ran away.
During a press briefing Mr Varadkar said he was glad the interview finished before the incident happened.
“I thought it was Avril Lavigne at first when I saw this girl approaching with a skateboard and a smoothie,” he said.
Mr Varadkar added that he believes the Gardaí will want to investigate the incident.
Social media users condemned the “vile” attack on Twitter.
“Vile unacceptable behaviour. We’ve had enough politically motivated violence for decades,” wrote one Twitter user.
“Acts like this cannot be tolerated in a civilised society. Stiff sentence and jail time required.”
Former presidential candidate Gavin Duffy said it was a “horribly uncouth thing to do to Tánaiste Leo Varadkar”.
“This is an attack on our democracy not him,” he said on Twitter.
“It’s reported it was coffee but it could have been anything including acid. We need to better protect our politicians.”
It comes after Mr Varadkar warned that the number of Covid-19 cases in Dublin is getting serious again.
The National Public Health Emergency Team said 253 new cases of the virus were confirmed in the last 24-hour reporting period, 116 of which were in Dublin.
“We’ve seen a marked increase in the number of Covid cases confirmed in Ireland, particularly, though not exclusively in the Dublin area, where the number of new cases has trebled in the space of two weeks,” said Mr Varadkar.
The Minister for Enterprise, Trade and Employment also announced a number of funding initiatives to help Dublin businesses.
He added: “Some people have sadly been laid off for a second time in one year. For some businesses who were just getting up and running again, having to close again and starting to wonder if their businesses can ever survive.
“For people who might be laid off today or tomorrow, I want to assure you that you are eligible for the Pandemic Unemployment Payment and in some cases your employer may decide to keep you on for those three weeks using the wage subsidy (scheme).
“For businesses, I know this is going to be really tough. It’s not what you expected this September and we are going to stand behind you.”