With the continuous intensification of marine traffic worldwide, whale-vessel collisions at sea (or “ship strikes”) have become one of the primary causes of mortality for cetaceans and a widely recognised cause of concern for human safety and economic losses. The Mediterranean Sea is a global hotspot for whale-vessel collisions, with one of the highest rates involving large cetaceans, especially the endangered fin whales (Balaenoptera physalus) and sperm whales (Physeter macrocephalus). Evidence indicates that both species are experiencing higher chances of a fatal collision than what predictions have estimated so far, with ship strikes being the main human-induced threat in the area. Regional and international organisations have stressed the need to address the issue by investigating the projected impacts of ship strikes on whale populations and by identifying possible mitigation measures to reduce chances of collision. Amongst the most popular and feasible options, there is the improvement of animal detection during navigation. Here, we present SEADETECT, a LIFE project that aims at developing an automated detection system to reduce vessel collision risk with marine mammals and unidentified floating objects (UFOs), combining state-of-the-art and novel technologies with existing approaches in the study of large whale ecology. This detection system consists of three elements; an automated onboard detection system composed of several sensors, a real-time passive acoustic monitoring (PAM) network at sea and a real-time detection-sharing and alert system (REPCET®). In this paper, we propose the development of a mitigation measure framework tailored for the issue of collision with fin and sperm whales in the north-western Mediterranean Sea, but that has the transferability features necessary for its application in other high-risk areas for ship strikes worldwide.