This was the first retrospective study to estimate the effect of increased pedestrian protection, autonomous emergency braking, and speed management to reduce serious injuries among pedestrians and bicyclists. More specifically, the aim was to estimate the injury mitigating effects of the following interventions: AEB with pedestrian and bicyclist detection, Euro NCAP pedestrian test score, active bonnet, traffic calming at pedestrian and bicycle crossings, and additionally, the combined effect of the above-mentioned treatments. The main source of data was the Swedish traffic data acquisition system (Strada), where information of road traffic crashes between passenger cars and pedestrians or bicyclists for the period 1 January 2003–31 December 2022 was obtained. Cars with optional fitment of AEB systems were identified, and the license registration number was used to access individual car equipment lists to identify whether the vehicle was equipped with AEB with pedestrian and/or cyclist detection. Information about traffic calming at pedestrian and bicycle crossings was obtained from the Swedish Transport Administration. The injury metric used was risk of permanent medical impairment (RPMI) of at least one percent and ten percent. RPMI captures the risk of long-term medical impairment based on a diagnosed injury location and Abbreviated Injury Severity (AIS) score. The relative difference between the mean values of RPMI (mRPMI1%+ and mRPMI10%+) was calculated and tested using an independent two sample t-test which was conducted for unequal sample sizes and variance. Although many results were found to be statistically non-significant, the following results were found to be significant at least at 90% level. Pedestrian mRPMI10%+ was reduced by 44% in speed zones ≤ 50 km/h comparing the group struck by cars equipped with AEB with pedestrian detection compared to the group struck by cars without the system. For cyclists, the mRPMI10%+ was reduced by 35% in speed zones ≤ 50 km/h. For crashes within ± 20 meters from a pedestrian or bicycle crossing, the AEB system reduced 60% of pedestrians mRPMI10%+ at crossings with good safety standard compared to crossings of poor safety standard. The comparison of cars with poor performance (1–9 points) in the NCAP pedestrian test and cars with a high score (28–36 points) showed that pedestrian mRPMI10%+ was reduced by 48% across all speed limits, and by 64% including only those aged ≤ 64 years. For bicyclists, a significant reduction of cyclist mRPMI10%+ was found comparing low scoring cars to high scoring cars in ≤ 30 km/h speed limit (-73%) and across all speed limits (-36%). Including only those aged ≤ 64 years, the reduction was 49%. For the active bonnet, a significant reduction of mRPMI1%+ by 24% was observed but given that the rate of helmet wearing was higher in the group struck by cars with active bonnet, this difference cannot be attributed to an effect of an active bonnet. The STA safety rating of pedestrian and bicycle crossings showed that overall pedestrian mRPMI1%+ was reduced by 15%, while cyclists mRPMI10%+ was reduced by 32% comparing crossings of high safety level to crossings of poor safety level. The analysis of combined interventions showed that the total reduction of pedestrians and cyclists mRPMI10%+ together was 69%, from 6.4% to 2%. This paper demonstrates that a road environment with adapted infrastructure and speed, combined with passenger car technologies that improve the safety for vulnerable road users, can create significant reductions of serious (long-term) injuries among pedestrians and bicyclists.