Street layout is consistently associated with adults' travel behaviors, however factors influencing this association are unclear. We examined associations of street layout with travel behaviors: walking for transport (WT) and car use; and, the extent to which these relationships may be accounted for by availability of local destinations. A 24-h travel diary was completed in 2009 by 16,345 adult participants of the South-East Queensland Household Travel Survey, Australia. Three travel-behavior outcomes were derived: any home-based WT; over 30 min of home-based WT; and, over 60 min of car use. For street layout, a space syntax measure of integration was calculated for each Statistical Area 1 (SA1, the smallest geographic unit in Australia). An objective measure of availability of destinations – Walk Score – was also derived for each SA1. Logistic regression examined associations of street layout with travel behaviors. Mediation analyses examined to what extent availability of destinations explained the associations. Street integration was significantly associated with travel behaviors. Each one-decile increment in street integration was associated with an 18% (95%CI: 1.15, 1.21) higher odds of any home-based WT; a 10% (95%CI: 1.06, 1.15) higher odds of over 30 min of home-based WT; and a 5% (95%CI: 0.94, 0.96) lower odds of using a car over 60 min. Local destinations partially mediated the effects of street layout on travel behaviors. Well-connected street layout contributes to active travel partially through availability of more local destinations. Urban design strategies need to address street layout and destinations to promote active travel among residents.