Johnny Timmons of Tupelo Water amp& Light said a switch was tripped around 2:30 p.m. and shut down the substation near Harrisburg Baptist Church.
The station is one of two powerful facilities that sends feeder lines throughout the city.
"When you lose that, you lose others like dominoes," Timmons said.
Traffic lights, businesses and homes in the city were without power for about 45 minutes.
Crews were searching the substation Monday afternoon for the exact cause of the outage. Timmons said possible causes include a lightning arrestor or bad equipment, as well as critters that might have affected the equipment.
"I hate to say it, but it could be a raccoon, opossum or any large animal like that," he said around 4:30 p.m. "But we haven't found anything yet."
The outage included places like the North Mississippi Medical Center's Wellness Center and traffic lights at Crosstown and at Main and Industrial.
All Tupelo schools were without power except Pierce Street and Filmore.
The outage left Magical Tans' Main Street location completely quiet and still.
"The rush had just slowed down, so it worked out great," said owner Barbara Taylor.
Across the street at the Link Centre, 107 Itawamba Community College nursing students were reviewing for their national licensure exams when it went dark, said instructor Joy Hand.
"These are three-day, six-hour reviews. They've been in school for two years, and they'll graduate on Saturday," she sad, "so it's pretty intense right now."
Many of the students were glad the lights went out.
"It's always nice to leave early," she said, "but they won't be happy tomorrow."