Engineered nanomaterials (ENMs) have tremendous potential in many fields, but their applications and commercialization are difficult to widely implement due to their safety concerns. Recently, in silico nanosafety assessment has become an important and necessary tool to realize the safer-by-design strategy of ENMs and at the same time to reduce animal tests and exposure experiments. Here, in silico nanosafety assessment tools are classified into three categories according to their methodologies and objectives, including (i) data-driven prediction for acute toxicity, (ii) fate modeling for environmental pollution, and (iii) nano-biological interaction modeling for long-term biological effects. Released ENMs may cross environmental boundaries and undergo a variety of transformations in biological and environmental media. Therefore, the potential impacts of ENMs must be assessed from a multimedia perspective and with integrated approaches considering environmental and biological effects. Ecosystems with biodiversity and an abiotic environment may be used as an excellent integration platform to assess the community- and ecosystem-level nanosafety. In this review, the advances and challenges of in silico nanosafety assessment tools are carefully discussed. Furthermore, their integration at the ecosystem level may provide more comprehensive and reliable nanosafety assessment by establishing a site-specific interactive system among ENMs, abiotic environment, and biological communities.