Pence said 79 cases have been confirmed, and, with more testing underway, "We expect that number to go up."
The cases have either been found in or are connected to Scott County, near the Kentucky border.
Every single confirmed case has been related to intravenous drug use of the opioid painkiller Opana, said Pence.
It's believed to be the worst HIV outbreak in the state history, said Brittany Combs, public health nurse at Scott County Health Department.
Pence, who has long opposed needle-exchange programs, said he would authorize a limited needle-exchange program in the county if local health officials decide that could combat further infections.
"This is all-hands-on-deck. This is a very serious situation," said Pence, who added that officials from the U.S. Centers for Disease Control and Prevention advised that a needle-exchange program should be set up.
"I'm prepared to make an exception to my long-standing opposition to needle-exchange programs," said Pence. "This is a public health emergency driven by intravenous drug use."
By declaring a public health disaster, Pence said that he was ordering relevant agencies to assist the state and county health department to fight the spread of HIV.
"For years, we've been fighting Opana in our county," Combs said. "[Doctors] won't give [prescriptions] for Opana unless absolutely necessary. Our doctors aren't writing for it. It's coming from out of county."
Combs said Opana is a painkiller normally given in pill form to patients, and it is used as "last resort" for pain relief. People recreationally using the drug often crush the pill and inject it for a longer-lasting high, according to Combs.
Everyone who has tested positive for HIV has admitted to intravenous drug use, although some have also had sex with other users, meaning it is not always clear how the virus was spread, according to Combs.
Pence noted Wednesday that the county usually sees just five cases a year, according to The Associated Press.
"This is a public health emergency, and I'm listening to my health department, I'm listening to the Centers for Disease Control and I'll make my decision based on the best science and the best way we can stop this virus and stop this outbreak in its tracks," Pence told the AP Wednesday.
A public awareness campaign to alert residents about the increase in HIV cases has started in the region. Pence emphasized that testing and treatment for HIV would be covered under the Indiana Medicare plan and asked anyone who thinks they were exposed to the virus to see a doctor or go to a clinic.
In addition to local and state health officials, the CDC has sent a team to the area to assist with the response.