"Three, two, one, liftoff!" said a NASA commentator as the spacecraft blasted off on a dark, foggy morning atop an Atlas V rocket at 4:05 am Pacific time (1105 GMT) from Vandenberg Air Force Base in California, marking NASA's first interplanetary launch from the US west coast.
The $993 million project aims to expand our knowledge of interior conditions on Mars, inform efforts to send human explorers there, and reveal how rocky planets like the Earth formed billions of years ago.
If all goes as planned during the 301 million mile (485 million kilometer) journey, the lander should settle on the Red Planet on November 26.
InSight is short for Interior Exploration using Seismic Investigations, Geodesy and Heat Transport.
"#Mars, here I come! Six months and counting to the Red Planet," said a message on InSight's Twitter account.
NASA chief scientist Jim Green said experts already know that Mars has quakes, avalanches and meteor strikes.
"But how quake-prone is Mars? That is fundamental information that we need to know as humans that explore Mars," Green said.