This lizard has a broad climatic tolerance. It is found from dry temperate to dry tropical areas, and in the more mesic Mediterranean climate of Israel's coastal plain, although it avoids areas exposed to saltwater (Stanner 2004). This species is found in sandy desert areas with some vegetation (including dunes), gravelly plains, steppe-like grassland habitats, dry river beds and valleys between dunes. It can be found in traditionally cultivated areas and is not affected by conversion to pastureland, however it only survives at the edges of cropland and it is unclear whether populations in these habitats are viable (Stanner 2004). The species lives in burrows which it may excavate itself. The presence of sandy or loose soils into which it can burrow appears to be "essential" to this lizard's persistence (Stanner 2004), although individual animals' home ranges may encompass areas with other soil types (Stanner 2004). Animals also use the sand to leave imprints which are used in communication, courtship and foraging (Stanner 2004 and refs therein). The lizard can also be found in urban areas where it forages through dumps. Animals are strictly seasonal, being active from March or April to October or November and hibernating within burrows for the rest of the year, with peak activity in May-June (Stanner 2004). Reports of year-round activity in the Shamiyah Desert (Iraq) are anecdotal and cannot be verified (Corkill 1928, Stanner 2004); however, it seems to be active year-round in sub-Saharan West Africa (Trape et al. 2012). Despite wide climatic variation across its range this activity pattern is largely consistent throughout the lizard's distribution, although there is geographical variation in relative activity levels by sex and age (Stanner 2004). Animals are diurnal and the length of the daily activity period varies across the monitor's range, possibly as a response to environmental conditions such as vegetation cover and prey availability (Stanner 2004).

Sexual maturity is generally attained at 3–4 years in males and 4–5 in females, although maturation at two years has been reported in Tunisia (Stanner 2004). The female lays between five and 20 eggs, but the interval between the first and last egg laid may be as long as 10 days (Stanner 2004). In the Kyzylkum Desert, females of Varanus griseus caspius do not have a regular annual or biannual reproductive cycle, but breed at irregular intervals (Stanner 2004). The other subspecies, V. g. griseus and V. g. koniecznyi, reportedly reproduce annually (Stanner 2004 and refs therein). Females excavate nesting burrows and protect them from other members of their species, but do not defend them against other predators. Once hatched, neonates remain within the nesting burrow until the following spring (Stanner 2004).

These large lizards are active predators, feeding on amphibians, lizards, small mammals (including rodents), bird eggs, snakes, and in some areas tortoise hatchlings (Stanner 2004), depending on prey availability. Less commonly monitors may forage on large arthropods, adult birds and, being strong swimmers and divers, on fish (Stanner 2004). The animal may also scavenge, but the extent to which carrion contributes to its diet is unclear (Stanner 2004).

Although predominantly desert-dwelling, the desert monitor occupies a variety of arid and semi-arid habitats including clay steppe, savanna and riverbeds up to elevations of 1,300 metres. A specific habitat requirement for this species is the presence of sand or soft soil in which tracks can be made for communication and orientation (Stanner 2004).

This is a widespread species of arid areas of North Africa and West and Central Asia. In northern Africa this species ranges from Rio de Oro in Western Sahara, Mauritania, northern Mali, and Niger in the west, throughout the Saharan desert region, to Egypt and northern Sudan in the east (Stanner 2004). From Egypt the species ranges northwards through the southern and eastern Levant and into Turkey (southeastern Anatolia), Iraq and Iran. The species is present throughout the Arabian Peninsula and occurs in Central Asia, represented by the subspecies Varanus griseus caspius, in southern Kazakhstan, Uzbekistan, Turkmenistan (except the extreme northwest), Afghanistan, Tajikistan and Kyrgyzstan; and by V. g. konieckzyi in Pakistan and northwestern India (Gujurat). It has been reported from Lebanon, but this record is considered questionable (Martens and Kock 1992). It is found up to 1,300 m asl.

This species was listed in Appendix I of CITES in 1975, and is protected by national legislation in a number of countries as well as by trade regulations controlling imports to the United States and European Union (Stanner 2004). In Jordan it is protected under Appendix I of the Hunting Law. It is also protected in Saudi Arabia. It is included in the Red Data Books of Kazakhstan (2010 - category 2, as a declining species), Uzbekistan (2009, as Vulnerable with a declining population and mosaic distribution), Kyrgyzstan (2006 - Critically Endangered, as a declining species at the limit of its range, represented by isolated populations), Turkmenistan (1999 - category 2, as a declining species) and Tajikistan (Critically Endangered). It is presumed to occur in a number of protected areas. Further research into the taxonomy of this apparent species complex is needed.