Background: Social isolation (SI) is an established risk factor for chronic disease and mortality. How people travel, including the modes of transportation they use, may shape opportunities for social interaction and influence the impacts of SI. This study assessed heterogeneity of the association between SI and mortality across primary modes of non-commute transportation. Methods: We analyzed cohort data from the UK Biobank, following participants aged 40-69 years from 2006 to 2022. SI at baseline was derived from three items and dichotomized. Cox models were used to estimate the association between SI and mortality, adjusting for socioeconomic factors, health behaviours, and comorbidities. Effect modification by participants' primary mode of non-commute transportation was assessed using interaction terms with SI. Results: There were 490,114 participants with complete baseline exposure data. SI was associated with increased hazard of all-cause (Hazard Ratio [HR] = 1.34, 95% Confidence Interval [CI]: 1.31-1.38) and cardiovascular mortality (HR = 1.49, CI: 1.41-1.57). The association with cardiovascular mortality was stronger among participants who only used public transport compared with those who only used a car (interaction HR = 1.17, CI: 1.00-1.37). In contrast, using a car alongside active or public transport, compared to using a car alone, attenuated the association between SI and all-cause mortality (interaction HR = 0.93, CI: 0.87-0.99). Conclusion: Mixed transport, including a car, showed the greatest reduction in the association between SI and all-cause mortality. Our findings motivate further exploration of the role of transportation modes in enhancing social connection, mobility, and health.