The women's bantamweight fight will be a rematch of a UFC 184 bout from February 2015 in which Holm beat Pennington via split decision.
Holm, the No. 3 ranked fighter in the UFC's bantamweight division, sports a 12-5 professional MMA record. She most recently lost to bantamweight champion Amanda Nunes at UFC 239 in July via first-round TKO.
Pennington, ranked No. 6 in the weight class, beat Irene Aldana via split decision in July. She is 10-7.
Holm's UFC debut was against Pennington, and Melbourne is the site of her shocking knockout win over the previously undefeated Ronda Rousey for the bantamweight title.
Although she's gone just 2-5 since the victory over Rousey, Holm has faced tough competition, including Nunes, Cris Cyborg and Germaine de Randamie.
Nunes is the best pound-for-pound fighter in the world, and Cyborg's only loss after 2005 occurred against Nunes. De Randamie is the No. 1 contender for the bantamweight title.
Pennington's only losses since the Holm defeat occurred against Nunes and de Randamie. The Nunes defeat ended in a fifth-round TKO, and the de Randamie loss occurred via unanimous decision in a catchweight fight after Pennington missed weight.
UFC 243 is headlined by a men's middleweight title unification bout between Robert Whittaker and Israel Adesanya.