Pelvic organ prolapse (POP) significantly impacts patients' quality of life, and current treatment options remain limited due to high recurrence rates, making the exploration of new therapeutic targets essential. Using data from the FinnGen cohort, we performed a proteome-wide Mendelian randomization (PW-MR) analysis. Through PW-MR and Bayesian colocalization analyses, we identified EFEMP1 and MFAP4 as potential key drug targets, with EFEMP1 potentially exerting a protective effect, whereas MFAP4 may be associated with an increased risk of POP. To further support these findings, we analysed single-cell RNA sequencing data to evaluate the expression patterns of EFEMP1 and MFAP4 in different cell populations. The analysis revealed that EFEMP1 and MFAP4 are specifically enriched in cell types involved in tissue remodelling and fibrosis. Findings of phenome-wide association studies indicated that the risk of side effects for these targets may be low, suggesting the safety of treatment focused on these targets. Preliminary molecular docking analysis findings suggested that EFEMP1 and MFAP4 may have strong binding affinities with candidate drugs, further supporting the feasibility of EFEMP1 and MFAP4 as drug targets. In conclusion, our findings indicate that EFEMP1 and MFAP4 are promising therapeutic targets for POP, providing important insights for the development of safe and effective treatments.