Anchorage is a challenge and essential issue for an orthodontist in determining the success of orthodontic treatment. Orthodontic anchorage is defined as resistance to unwanted tooth movement. Mini-implant is one of the devices that can be used as an anchor in orthodontic treatment. Many cases have reported successful treatment using mini-implant, but there are cases where mini-implants may fail. Failure of mini-implants can affect orthodontic treatment, and it is known that several factors may lead to mini-implant loss in orthodontic treatment. This systematic review aimed to determine the factors influencing mini-implant failure in orthodontic treatment. Articles were selected from electronic databases (PubMed, Google Scholar, The Cochrane Library, ScienceDirect) from January 2015 until 2023 according to the PRISMA method (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) under the PEOS (Population-Exposure-Outcome-StudyType) framework questions for systematic review. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42022337684). All data collected were in English, and filtering was done by eliminating duplicate data, meta-analysis, case reports, case series, mini-reviews, and animal studies. The analysis was further divided into three groups, that is, patient-related, implant-related, and operator-related and operator-related (A graphical abstract provided as a Supplementary information [available in the online version]). Twenty-one articles were identified according to the inclusion criteria in the form of retrospective, prospective, in vivo, and randomized controlled trial studies. Mini-implant failures due to patient-related showed six etiological factors, failures due to implant-related had eight etiological factors, and only one factor was operator-related, which may lead to mini-implant failure. The data was extracted without a computerized system and only in English. Mini-implant failure can be caused by many factors; we could not accuse one major factor as a cause. However, the quality or condition of the bones and oral hygiene are factors that play a significant role in obtaining the stability of implants. Mini-implant failure is highly influenced by poor oral hygiene and peri-implant inflammation. Comprehensive diagnostic prior to mini-implant insertion should be appropriately considered. This systematic review describes several factors that can influence mini-implant failure, divided into three groups: patient-related, implant-related, and operator-related (A graphical abstract provided as a Supplementary information [available in the online version]).