If the Iraqi population is "threatened by the use of force outside the law, then we will intervene militarily," he said in an interview with the Associated Press news agency on Saturday.
Iraq's Kurdish region plans to hold the referendum on support for independence from Iraq on September 25 in three governorates that make up their autonomous region, and in disputed areas controlled by Kurdish forces, but which are claimed by Baghdad.
"If you challenge the Constitution and if you challenge the borders of Iraq and the borders of the region, this is a public invitation to the countries in the region to violate Iraqi borders as well, which is a very dangerous escalation," Abadi said.
The leaders of Iraq's Kurdish region have said they hope the referendum will push Baghdad to come to the negotiating table and create a path for independence. However, Abadi said such negotiations would likely be complicated by the referendum vote.
"It will make it harder and more difficult," he said, but added: "I will never close the door to negotiations. Negotiations are always possible."
In a statement released late on Friday, the White House called for the Kurdish region to abandon the referendum "and enter into serious and sustained dialogue with Baghdad".
"Holding the referendum in disputed areas is particularly provocative and destabilising," the statement read.
Tensions between Erbil and Baghdad have flared in the lead-up to the September 25 vote.
Masoud Barzani, the president of Iraq's autonomous Kurdish region, has repeatedly threatened violence if Iraqi military or Shia militias attempt to move into disputed territories that are now under the control of Kurdish fighters known as Peshmerga, specifically the city of Kirkuk.
"It's chaotic there," Muhammad Mahdi al-Bayati, a senior leader of Iraq's mostly Shia fighters known as the popular mobilisation forces, said earlier this week, describing Kirkuk.
Bayati's forces - sanctioned by Baghdad, but many with close ties to Iran - are deployed around Kirkuk as well as other disputed territories in Iraq's north.
"Everyone is under pressure," he said, explaining that he feared a rogue group of fighters could trigger larger clashes. "Anything could be the spark that burns it all down."
Abadi said he is focused on legal responses to the Kurdish referendum on independence. Earlier this week, Iraq's parliament rejected the referendum in a vote boycotted by Kurdish politicians.
Iraq's Kurds have long held a dream of statehood. Oppressed under Saddam Hussein, whose military in the 1980s killed at least 50,000 of them, many with chemical weapons, Iraq's Kurds established a regional government in 1992 after the US enforced a no-fly zone across the north following the Gulf War.
After the 2003 US-led invasion overthrew Hussein, the region secured constitutional recognition of its autonomy, but remained part of the Iraqi state.
Abadi began his term as prime minister after Mosul had fallen to the Islamic State of Iraq and the Levant (ISIL) group, plunging Iraq into the deepest political and security crisis since the sectarian bloodshed that followed the 2003 US-led invasion.
Over the past three years, Iraqi forces slowly retook territory from ISIL, also known as ISIS.
In July, Iraqi forces retook Mosul and effectively shattered ISIL's self-declared territorial caliphate.
However, the military successes have come at great cost. In the fight for Mosul alone between 970 and 1,260 civilians were killed and more than twice as many members of Iraq's security forces lost their lives, Abadi told the Associated Press news agency.
Despite territorial losses, ISIL continues to carry out attacks in Iraq.
On Thursday, an attack claimed by ISIL at a checkpoint and restaurant in southern Iraq left more than 80 killed and 93 wounded.
Years of war have left more than three million people displaced. Cities, towns and villages retaken from ISIL lie in ruins and the forces, made powerful by the arms and training that flooded Iraq to fight the armed group, now attempt to leverage that influence.