Police have launched a manhunt after the attacker fled the scene, detectives confirmed.
The priest was shot twice at around 4pm local time on Saturday as he was closing the church for the evening.
He is now being treated in a local hospital with life-threatening injuries after being hit in the abdomen.
The assailant was alone and fired from a hunting rifle, an official told reporters.
Police locked down the neighbourhood around the church and warned the public on Twitter to stay away.
The motive for the attack is unclear.
President Emmanuel Macron has deployed thousands of soldiers to protect sites such as places of worship and schools.
Antoine Callot, the pastor at another Greek Orthodox church in Lyon, identified the wounded priest as Nikolas Kakavelakis, a 45-year-old father of two.
Mr Callot told the Associated Press that the Greek Orthodox community in Lyon has not received any threats, but said he immediately asked police for security protection at his church after the shooting.
“We are anxious and anguished. It’s really horrible,” he said. “Now we need to hide and be careful.”
Residents and a local police patrol heard shots near the church, and when officers arrived they saw an individual running away and found the wounded priest by the back door of the church, the Lyon prosecutor said in a statement.
Prime Minister Jean Castex reiterated government promises to deploy military forces at religious sites and schools.
Macron to deploy 4,000 more soldiers after three killed in church attack
He said French people can “count on the nation to allow them to practise their religion in full safety and freedom”.
Seeking to calm tensions and to explain France’s defence of the prophet cartoons, Mr Macron gave an interview broadcast on Saturday on Arabic network Al-Jazeera.
The president also tweeted that “our country has no problem with any religion”, adding: “No stigmatisation: France is committed to peace and living together in harmony”.
The Greek Foreign Ministry said in a statement: “We condemn the attack against an Orthodox priest of Greek origin near the Church of the Annunciation in Lyon, France. The Ministry of Foreign Affairs is in constant contact with the competent French authorities.”