Archaeological evidence suggests that the interior of the Australian continent was first occupied during the Mid-Holocene. It is agreed that the general climate of Australia during this time was warmer and wetter, but the absence of reliable palaeoclimatic proxies in the arid interior makes precise localized reconstructions difficult. In addition, the main determinants of the patterns of human settlement of the interior is not well known. This study presents a thorough review of palaeoenvironmental proxy data and archaeological data of Mid-Holocene Australia coupled with hydrological and palaeoclimatological modeling approaches to determine what most strongly influenced the patterns of human occupation of the interior. This paper is the first to employ a reconstructive groundwater table depth model to determine if permanent and accessible subsurface water influenced the locations of human settlement. Results show that most of the Australian continent experienced wetter conditions during the Mid-Holocene which corresponds with an enhanced Northern Australian Monsoon. This study determines that groundwater table depth and elevation were the predominant determinants of human settlement patterns of the Australian interior.