Background: Due to its various resistance mechanisms, Pseudomonas aeruginosa is the most prevalent opportunistic infection that kills hospitalized patients. Thus, therapeutic options become limited. Objective: The study aimed to estimate the antibiofilm effectiveness of Conocarpus erectus leaf extracts against MDR P. aeruginosa isolates and examines pelA and algD gene expression. Subjects and Methods: One hundred-fifty clinical samples were collected from five Baghdad hospitals between September 2021 and January 2022. Samples were grown on different mediums. Despite cetrimide agar's ability to detect P. aeruginosa, only 83 isolates developed at 42°C. VITEK 2 compact system identification followed. This study examined 83 of P. aeruginosa isolates for resistance vs 10 medications. Disk diffusion was used for this investigation. Results: The results showed that P. aeruginosa isolates were most resistant to Ceftriaxone, Amoxicillin-Clavulanic acid, and Trimethoprim. Microtiter plate biofilm detection is done with 10 multi-drug-resistant isolates. All isolates produced significant biofilm. Maceration and Soxhlet equipment produced methanolic and aqueous extracts. The phytochemical screening of Conocarpus erectus revealed flavonoids, phenols, alkaloids, tannins, glycosides, and saponins in methanolic and aqueous extracts. 32 mg/ml Conocarpus erectus methanolic leaf extract prevented clinical P. aeruginosa biofilm development. After treatment with the sub-MIC of the methanolic extract, P. aeruginosa's biofilm-forming genes pelA and algD had minimal expression. Conclusion: This study demonstrated that Conocarpus erectus methanolic extracts contain significant phytochemical content, making them therapeutic. The antibiofilm compound in Conocarpus erectus extract downregulates the algD and pelA genes in P. aeruginosa despite antibiotic resistance.