Charles Wesco from Warsaw in Indiana was going shopping with his wife, one of his sons and another person when the car they were travelling in came under attack.
It happened near the town of Bamenda in the country's north-west - a region which has been in the grip of a bloody insurgency during recent years.
Dave Halyaman, an assistant pastor from Mr Wesco's home church, Believers Baptist Church, described the shooting as a "terrible tragedy".
He told the Washington Post: "While this is a terrible tragedy and we want the perpetrators to face justice, we are trusting God that He is going to do something good through all of this, though we just really don't know what it would be.
"There's no telling why he was singled out and shot. There's just no way to tell at this point."
At least two shots struck Mr Wesco. The father-of-eight was transferred to a hospital but doctors were unable to resuscitate him.
A statement released by the Cameroonian Defence Minister Joseph Beti Assomo said a "group of terrorists" were to blame.
Mr Assomo added that government forces had tracked the perpetrators down before four were killed in an ensuing crossfire.
Some reports on social media have blamed security forces, while others have accused armed separatists of responsibility.
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