Systems and methods are disclosed for antenna optimization in an information handling system. A portable information handling system includes a chassis and a plurality of antennas coupled to the chassis. The plurality of antennas is capable of communicating in a multiple-input and multiple-output (MIMO) antenna configuration with a wireless-enabled device. The system includes an antenna control module communicatively coupled to the plurality of antennas. The antenna control module is configured to detect a change in at least one of a physical configuration of the chassis and an environment surrounding the portable information handling system, the change affecting a performance one or more of the plurality of antennas. The antenna control module is also configured to, based on the change, update a MIMO antenna list from the plurality of antennas. The MIMO antenna list represents active antennas for communicating with the wireless-enabled device.