An Amber Alert has been declared in Calgary for a missing five-year-old boy and his grandparents.

Five-year-old Nathan O'Brien has blond curly hair and brown eyes and was wearing peach-coloured shorts and a striped blue hoodie.

Alvin Liknes, 66, has grey-blond hair and was last seen wearing black sports shorts. He walks with a slight limp. Kathy Liknes, 53, has red-brown hair and green eyes and was last seen wearing pyjamas. Both are considered missing.

Nathan was last seen wearing peach-coloured shorts and a striped blue hoodie, say police. (Calgary Police Service)

The child's mother went to the grandparents' home in the southwest Calgary community of Parkhill at 10 a.m. MT, but no one was there.

“Evidence found at the residence suggests the disappearance of all three family members may be suspicious," said Calgary Police Service spokesman Kevin Brookwell.

Nathan's mother dropped him off at his grandparent's house for a sleepover Sunday night at 10 p.m. MT.

"When we went to the address and after speaking with family the home wasn't in the condition it would typically be left in, and there's some indication the occupants did not leave under their own volition," said Brookwell.

"All the vehicles are accounted for, no information to go on at this time, that's why we're reaching out to the public if they saw anything suspicious."

Anyone with information can call the Calgary Police Service at 403-266-1234 or Crime Stoppers at 1-800-222-8477.

The homicide unit is looking into the case, but Brookwell says that's not unusual.

"[It's] because of the circumstances and nobody has heard from them, no information despite everyone's best efforts," he said.

"We'll remain optimistic we'll find them, could be others involved, I don't want to speculate."

Police searched the area and said all family members they have spoken to are co-operating.