Background: Despite the expanding use of orthopedic devices and the application of strict pre- and postoperative protocols, the elimination of postoperative implant-related infections remains a challenge. Objectives: To identify and assess the in vitro and in vivo properties of antimicrobial-, silver- and iodine-based implants, as well as to present novel approaches to surface modifications of orthopedic implants. Methods: A systematic computer-based review on the development of these implants, on PubMed and Web of Science databases, was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: Overall, 31 in vitro and 40 in vivo entries were evaluated. Regarding the in vitro studies, antimicrobial-based coatings were assessed in 12 entries, silver-based coatings in 10, iodine-based in 1, and novel-applied coating technologies in 8 entries. Regarding the in vivo studies, antimicrobial coatings were evaluated in 23 entries, silver-coated implants in 12, and iodine-coated in 1 entry, respectively. The application of novel coatings was studied in the rest of the cases (4). Antimicrobial efficacy was examined using different bacterial strains, and osseointegration ability and biocompatibility were examined in eukaryotic cells and different animal models, including rats, rabbits, and sheep. Conclusions: Assessment of both in vivo and in vitro studies revealed a wide antimicrobial spectrum of the coated implants, related to reduced bacterial growth, inhibition of biofilm formation, and unaffected or enhanced osseointegration, emphasizing the importance of the application of surface modification techniques as an alternative for the treatment of orthopedic implant infections in the clinical settings.