Using Unmanned Aerial Vehicles (UAVs), commonly referred to as “drones”, as a supplementary mode for last-mile deliveries has been a research focus for some years now. Motivation lies in the reduced dependency on Conventional Vehicles (CVs) and fossil fuels and in serving remote areas and underprivileged populations. We are building a flexible, modular framework for integrated CV-UAV parcel delivery operations planning that is responsive to infrastructure and demand and offers an open and practical tool for future adaptations. The entire model and solution methodology are practical tools for decision making and strategic planning, with novelties such as the variable Launch Site types for Launch and Recovery Operations (LAROs), the tailored Assignment and Routing Optimization nested GA, the consideration of airspace restrictions of any shape and size, the inclusion of GIS tools in the process, the modularity of the platform, and most importantly, the inclusion of all the above in a single, comprehensive, and holistic approach. Because of the need for safe UAV deployment sites and the high presence of restricted airspace zones in urban environments, the intended field of application is assumed to be the delivery of small packages in rural and under-connected areas, the execution of inter-city deliveries, and the expansion of a city’s original service range. A single CV is equipped onboard with UAVs, while special locations, such as Remote Depots (RDs) with UAVs and Virtual Hubs (VHs) for UAV deployment facilitation, are introduced. The framework considers the presence of Restricted Zones (RZs) for UAV flights. Part of the methodology is implemented in a GIS environment, taking advantage of modern tools for spatial analysis and optimal path planning. We have designed a tailored nested GA method for solving the occurring mode assignment and vehicle routing optimization problems and have implemented our workflow on a devised case study with benchmark characteristics. Our model responds well to unfavorable network types and demand locations, while the presence of RZs notably affects the expected solution and should be considered in the decision-making process.