Herbal remedies have risen for decades in developed and developing countries. In this systematic review, the herbs such as cannabis, St. John's wort, kava, turmeric, grapefruit, bitter orange, ginger, garlic, and Chinese Herbal tea are discussed to interact with medicines and potentially cause adverse reactions. This study aimed to investigate the occurrence and prevalence of drug/NP interactions in healthy volunteers or patients with comorbidities in elderly populations above 65. A systematic literature review was conducted using PubMed, Google Scholar, Scopus, Cochrane, and MedRxiv databases, from May 2022 until July 2022. Studies investigating drug/NP-related problems (DNRP) in healthy patients or patients with comorbidities were included. The data obtained was then commenced with the quality assessment by the Joanna Briggs Institute (JBI) tool. The inclusion criteria comprised six studies demonstrating that most drug classes associated with DNRP were represented by Selective Serotonin reuptake inhibitors (SSRIs), kinase inhibitors, and anti-neoplastic agents. Factors linked to DNRP are age, the number of medications, gender, five or more prescribed drug, presence of comorbidity, underestimation of potential adverse events, and length of hospitalization. This systematic review has proven that DNRPs may occur due to herb-drug interaction or multi-medication consumption. Limitations such as patients not disclosing their DNRPs to pharmacists may affect the investigation. At the same time, larger sample sizes are required to unfold the real problem in future studies.