Medication self-management problems such as the inability to correctly obtain, understand, organize, administer or monitor medication can result in negative patient outcomes. However, supportive tools for healthcare providers to assist patients with medication self-management problems are lacking. This study aimed to develop recommendations for healthcare providers to support patients with polypharmacy who experience medication self-management problems. A three-phase study was conducted starting with (1) the mapping of medication self-management problems, followed by (2) a scoping review providing a list of relevant interventions and actions for each respective problem and (3) a three-round modified e-Delphi study with experts to reach consensus on the relevance and clarity of the recommended interventions and actions. The cut-off for consensus on the relevance and clarity of the recommendations was set at 80% expert agreement. Experts could propose additional recommendations based on their professional experience and expertise. The experts (n = 23) involved were healthcare professionals (i.e., nurses, pharmacists, and physicians) with specific expertise in medication management of patients with polypharmacy. Simultaneous with the second e-Delphi round, a panel of patients with polypharmacy (n = 8) evaluated the usefulness of recommendations. Results obtained from the patient panel were fed back to the panel of healthcare providers in the third e-Delphi round. Descriptive statistics were used for data analysis. Twenty medication self-management problems were identified. Based on the scoping review, a list of 66 recommendations for healthcare providers to support patients with the identified medication self-management problems was composed. At the end of the three-round e-Delphi study, the expert panel reached consensus on the relevance and clarity of 67 recommendations, clustered according to the six phases of the medication self-management model by Bailey et al. In conclusion, this study resulted in a guidance document including recommendations that can serve as a resource for healthcare providers to support patients with polypharmacy in case of medication self-management problems. Future research should focus on the evaluation of the feasibility and user-friendliness of the guide with recommendations in clinical practice.