The gunshots were reported at noon on Monday, local time.
Police arrived within four minutes and immediately saw what appeared to be three people who appeared to be dead outside, Police Chief Scott Wahl said.
The children at the mosque's school are all reported to have survived.
"All the children are safe. We have three confirmed dead adults," Wahl said at a press conference.
As the police began their work, with the shooting considered to be ongoing, an alarm came in reporting more shots fired a short distance away. A gardener was shot at but not hit. Then a third report of gunshots came from another nearby location.
A vehicle was found there with what we believe to be the two shooters, both deceased, Police Chief Scott Wahl said.
The mosque's chairman told The New York Times in an email that one of the victims was a security guard.
Police are investigating the incident as a suspected hate crime, according to the AP.
The circumstances and details of what happened and how will be clarified in the coming days, Police Chief Scott Wahl said.
Television images from the scene showed a massive police force swarming outside the mosque and children being escorted out of the facility's school.
US President Donald Trump described the incident as "horrible".
"I've had some early updates, but we'll go back and look at it very carefully," he told reporters, according to AFP.
The mosque is, according to its own website, the largest in San Diego.
