Abiotic, biotic and human influences are factors that can affect animal home ranges. We calculated home range sizes of adult giraffes in the Tarangire-Manyara region of northern Tanzania (N ¼ 132 giraffes with data collected over 6 years), and investigated correlations between home range sizes and environmental and anthropogenic factors (for a subset of N ¼ 71 giraffes). We used a 95% kernel utilization distribution to define home ranges and modelled home range size as a function of environmental and anthropogenic predictors using multiple linear regression and model selection. We also computed home range sizes of giraffes using 100% minimum convex polygons to compare with estimates from previously published studies, and tested the relationship between rainfall and home range sizes of giraffes across Africa. Average kernel home range sizes were 114.6 km2 for females (N ¼ 109) and 157.2 km2 for males (N ¼ 23). Adult female giraffe home range sizes (N ¼ 67) were negatively correlated with distance to densely populated towns. Females living closer to towns had significantly larger home ranges, suggesting a need to range farther to avoid human-impacted areas while obtaining critical resources. No such relationship was evident with bomas, which are homesteads built by indigenous pastoralist people, suggesting that female giraffes are tolerant of traditional land uses. Mean annual rainfall explained 74% of the variation in home range sizes of giraffes across the African continent, with smaller home ranges in regions with higher rainfall and thus greater productivity, providing additional evidence that access to critical resources mediates home range size of this megaherbivore. Quantifying home range sizes and identifying ecological and anthropogenic factors affecting space use can provide insights into mechanisms driving use of space and help wildlife managers make informed decisions that improve conservation plans for at risk species such as giraffes.