We examined the trade-offs between in-car aerosol concentrations, ventilation and respiratory infection transmission under three ventilation settings: windows open (WO); windows closed with air-conditioning on ambient air mode (WC-AA); and windows closed with air-conditioning on recirculation (WC-RC). Forty-five runs, covering a total of 324 km distance on a 7.2-km looped route, were carried out three times a day (morning, afternoon, evening) to monitor aerosols (PM2.5; particulate matter WC-AA > WC-RC) due to the ingress of polluted outdoor air on urban routes. A clear trade-off, therefore, exists for the in-car air quality (icAQ) versus ventilation; for example, WC-RC showed the least aerosol concentrations (i.e. four-times lower compared with WO), but corresponded to elevated CO2 levels (i.e. five-times higher compared with WO) in 20 mins. We considered COVID-19 as an example of respiratory infection transmission. The probability of its transmission from an infected occupant in a five-seater car was estimated during different quanta generation rates (2–60.5 quanta hr-1) using the Wells-Riley model. In WO, the probability with 50%-efficient and without facemasks under normal speaking (9.4 quanta hr-1) varied only by upto 0.5%. It increased by 2-fold in WC-AA (<1.1%) and 10-fold in WC-RC (<5.2%) during a 20 mins trip. Therefore, a wise selection of ventilation settings is needed to balance in-car exposure in urban areas affected by outdoor air pollution and that by COVID-19 transmission. We also successfully developed and assessed the feasibility of using sensor units in static and dynamic environments to monitor icAQ and potentially infer COVID-19 transmission. Further research is required to develop automatic-alarm systems to help reduce both pollutant exposure and infection from respiratory COVID-19 transmission.