Leptospirosis is a bacterial zoonosis that poses an increasing global public health risk. Pacific Island communities are highly vulnerable to leptospirosis outbreaks, yet the local drivers of infection remain poorly understood. We conducted a systematic review to identify the drivers of human Leptospira infection in the Pacific Islands. There were 42 included studies from which findings were synthesized descriptively. In tropical Pacific Islands, infections were a product of sociodemographic factors such as male gender/sex, age 20 to 60 years, Indigenous ethnicity, and poverty; lifestyle factors such as swimming, gardening, and open skin wounds; and environmental factors, including seasonality, heavy rainfall, and exposure to rodents, cattle, and pigs. Possible mitigation strategies in these islands include strengthening disease reporting standards at a regional level; improving water security, rodent control, and piggery management at a community level; and information campaigns to target individual-level drivers of infection. By contrast, in New Zealand, exposures were predominantly occupational, with infections occurring in meat and farm workers. Accordingly, interventions could include adjustments to occupational practices and promoting the uptake of animal vaccinations. Given the complexity of disease transmission and future challenges posed by climate change, further action is required for leptospirosis control in the Pacific Islands.