Simple Summary: The main treatment for extramammary Paget’s disease (EMPD) is still surgery, but this neoplasm usually spreads beyond the clinical surroundings of the lesion, and achieving histopathologically free margins can be challenging and requires mutilating surgery. Moreover, the recurrence rate of the disease is high, reflecting its multifocal nature. Topical immunotherapy could be an alternative treatment for EMPD. The aim of this systematic review was to assess the effectiveness of topical imiquimod in the clinical response of EMPD patients and to describe the management of topical imiquimod in EMPD. Learning about non-surgical treatments such as topical imiquimod can help clinicians manage EMPD and find a balance between disease resolution and treatment morbidity. Abstract: Extramammary Paget’s disease (EMPD) is subclinical in extent and multifocal in nature. There is no global consensus for treatment, so its management represents a challenge in clinical practice. Therefore, we conducted a systematic review through the main electronic databases to assess the effectiveness of topical imiquimod in cutaneous EMPD and to discuss its management. Finally, 24 studies involving a total of 233 EMPD patients treated with topical imiquimod were selected. The topical imiquimod response rate was 67%, and the complete response (CR) rate was 48%. Patients were treated with a three–four times a week regimen in most cases, ranging between 2 to 52 weeks. In addition, imiquimod was applied as an adjunctive treatment in 21 patients, achieving a CR rate of 71%. Consequently, imiquimod therapy could achieve a good response ratio as a first-line treatment, as adjuvant and neo-adjuvant therapy, and as a treatment for recurrent disease. The heterogeneity between studies and the lack of a control arm made it impossible to conduct a meta-analysis. To improve the quality of evidence on EMPD, multicenter studies are essential to collect a larger number of patients and, consequently, obtain high-quality evidence to standardize treatment. The Prospero registration number is CRD42023447443.