This paper addresses the capacitated vehicle routing problem with time-window and three-dimensional loading constraints in land–sea transport (3L-CVRPTWLS, which is an extension of the 3L-CVRP) to minimize the total cost of land–sea transport. The 3L-CVRPTWLS considers the online packing environment and port-of-destination (POD) constraint, which are clearly of practical significance in freight distribution. Due to its high degree of combinatorial complexity, the literature on this problem is very limited. To solve the 3L-CVRPTWLS, we develop a general deepest-bottom-left-fill (DBLF) and layer heuristic for packing and a hybrid variable-neighborhood tabu search for the routing phase (HLVNTS) based on the “packing first, routing second” (P1R2) strategy. HLVNTS reduces the average total number of vehicles by 2.51% and the average total travel distance by 27.62% in a shorter amount of time. The experimental results show that the proposed algorithm performs well in the tested instances in terms of both computational efficiency and solution quality. Moreover, we evaluate the impact of the POD constraint on the total transportation cost. This study may provide some important support for the sustainable development of land–sea transport and help to protect the environment.