The considerable increase in parcel deliveries has negatively impacted the accessibility and livability of cities. One solution strategy is to decouple short-distance from long-distance shipping so that last-mile transport can be performed with low-footprint vehicles. Such solutions are referred to in the literature as multi-echelon distribution systems. This study introduced a new variant of the two-echelon vehicle routing problem that considers multiple alternative transport modes as well as multiple commodities over a multi-period time horizon, where customers can obtain their commodities from any store. We referred to this problem as the two-echelon multi-commodity multimodal vehicle routing problem (MCM-2E-VRP). The objective of service providers is to minimize total generalized costs while satisfying customer requirements. We formulated this as a mathematical model based on a space–time network and introduced a random utility discrete choice model to capture variations in performance and preferences. We developed an adaptive large-neighborhood search (ALNS) algorithm to provide solutions for newly generated MCM-2E-VRP instances based on the Beijing Yizhuang transportation network. Extensive numerical experiments were conducted to verify the effectiveness of the proposed model and algorithm. A sensitivity analysis revealed some policy-relevant findings regarding the effects of store distribution and vehicle capacity.