Cyber-Physical Systems (CPSs) represent a systems category developed and promoted in the maritime industry to automate functions and system operations. In this study, a novel Combinatorial Approach for Safety Analysis is presented, which addresses the traditional safety methods’ limitations by integrating System Theoretic Process Analysis (STPA), Events Sequence Identification (ETI) and Fault Tree Analysis (FTA). The developed method results in the development of a detailed Fault Tree that captures the effects of both the physical components/subsystems and the software functions’ failures. The quantitative step of the method employs the components’ failure rates to calculate the top event failure rate along with importance metrics for identifying the most critical components/functions. This method is implemented for an exhaust gas open loop scrubber system safety analysis to estimate its failure rate and identify critical failures considering the baseline system configuration as well as various alternatives with advanced functions for monitoring and diagnostics. The results demonstrate that configurations with SOx sensor continuous monitoring or scrubber unit failure diagnosis/prognosis lead to significantly lower failure rate. Based on the analysis results, the advantages/disadvantages of the novel method are also discussed. This study also provides insights for better safety analysis of the CPSs.