The shooting in southern Kentucky has been ruled an accident, Kentucky State Police Trooper Billy Gregory said.
"It's just one of those nightmares," he said, "a quick thing that happens when you turn your back."
Young children in the area are often introduced to guns at an early age, Gregory said.
"In this part of the country, it's not uncommon for a 5-year-old to have a gun or for a parent to pass one down to their kid," he said.
On Wednesday, state police were still investigating toddler Caroline Sparks' death, CNN affiliate WLEX reported.
Her family kept the Crickett rifle in what they considered to be a safe spot, Cumberland County Coroner Gary White told the CNN affiliate.
The boy was playing with it Tuesday when it accidentally went off and killed his sister, White said.
"The little Crickett rifle is a single-shot rifle, and it has a child safety," White told CNN. "It's just a tragic situation."
The Crickett website features three .22-caliber rifle models for kids, with shoulder stock colors ranging from pink to red, white and blue swirls. "My first rifle" is the company's slogan.
Family members Wednesday described the shooting as an accident.
"He just picked (the gun) up before he realized it," grandmother Linda Riddle told WLEX.
Riddle said her granddaughter enjoyed singing and playing outdoors, and she loved her brother.
"It's just tragic," uncle David Mann told the CNN affiliate. "It's something that you can't prepare for."
Riddle said she is devastated, but comforted knowing that her granddaughter is in a better place.
"It was God's will. It was her time to go, I guess," she told WLEX. "I just know she's in heaven right now and I know she's in good hands with the Lord."
Caroline Sparks' death comes after two other incidents in recent months involving young children shooting others. In early April, a 4-year-old boy in Tennessee shot and killed a 48-year-old woman, and just days later, 6-year-old Brandon Holt was killed in New Jersey after being shot in the head by his 4-year-old playmate.
CNN's Catherine E. Shoichet, Laura Batchelor, Julia Talanova, Alanne Orjoux and Julie In contributed to this report.
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