Introduction: This review and case report presents the treatment of two large cystic periapical lesions using simple aspiration technique for decompression and triple antibiotic paste for disinfection of the root canal system. Methods: A non-surgical approach was followed for the two large cystic periapical lesions. Simple aspiration irrigation technique along with lesion sterilization therapy with triple antibiotic paste was used without any surgical intervention. Results: Complete periapical healing of both the cyst like periapical lesions occurred without any surgical intervention. A 1 year follow-up radiograph showed complete healing of the lesion. Conclusion: Pathogenesis, histology, and molecular cell biology of inflammatory apical true cysts are not different from pocket cysts. Therefore, inflammatory apical true cysts might regress after nonsurgical root canal therapy by the mechanism of apoptosis or programmed cell death, similar to inflammatory pocket cysts. Non-surgical approach using a combination of Simple Aspiration technique and LSTR (lesion sterilization and tissue repair) technique was successful in healing large cyst-like periradicular lesions.