The goal of Universal Cross-Domain Retrieval (UCDR) is to achieve robust performance in generalized test scenarios, wherein data may belong to strictly unknown do-mains and categories during training. Recently, pre-trained models with prompt tuning have shown strong generalization capabilities and attained noteworthy achievements in various downstream tasks, such as few-shot learning and video-text retrieval. However, applying them directly to UCDR may not be sufficient to handle both domain shift (i.e., adapting to unfamiliar domains) and semantic shift (i.e., transferring to unknown categories). To this end, we propose Prompting-to-Simulate (ProS), the first method to apply prompt tuning for UCDR. ProS employs a two-step process to simulate Content-aware Dynamic Prompts (CaDP) which can impact models to produce generalized features for UCDR. Concretely, in Prompt Units Learning stage, we introduce two Prompt Units to individually capture domain and semantic knowledge in a mask-and-align way. Then, in Context-aware Simulator Learning stage, we train a Content-aware Prompt Simulator under a simulated test scenario to produce the corresponding CaDP. Extensive experiments conducted on three benchmark datasets show that our method achieves new state-of-the-art performance without bringing excessive parameters. Code is available at https://github.com/fangkaipeng/ProS.