The four vehicle pile-up happened after 6:00 Friday night in Putnam County on I-70 near US-231 in Cloverdale.
Indiana State Police say a semi truck plowed into stopped cars in a construction zone.
The semi driver was not wearing a seatbelt and was thrown out of his truck. He's in critical condition in an Indianapolis hospital.
One of the cars he struck caught fire. Bystanders pulled the mom out and performed CPR, but they couldn't reach her child through the flames.
Police confirm the 49-year-old woman and her 3-year-old daughter died in the crash.
The 47-year-old father was airlifted to the hospital.
One of the closed eastbound lanes of I-70 near Cloverdale has since reopened.