Background/Objectives: The European Medicines Agency (EMA) approved new antimicrobial agents against Gram-negative bacteria, such as cefiderocol, eravacycline, and aztreonam-avibactam, for the treatment of infection with carbapenem-resistant (CR)/carbapenemase-producing microorganisms. However, real-life data regarding their efficacy in clinical settings is still scarce. This systematic review refers to relevant studies aiming to establish whether these novel therapeutic options remain viable alternatives in treating infections caused by highly resistant Gram-negative microorganisms. Methods: To conduct our study, Pubmed, Web of Science, Science Direct, and ClinicalTrials.gov were screened. Studies published between the validation report provided by EMA for each molecule and 15 September 2024 were selected and then assessed based on their reference to patient clinical outcomes. The main inclusion criteria were first-hand results of their clinical experience with the molecules, treatment regimens, and clinical and microbiological outcomes (mortality, cure rates, and recurrence). Exclusion criteria included the absence of clinical data, studies not belonging to the specified time frame, and others. Results: Most studies using eravacycline and cefiderocol demonstrated at least non-inferiority regarding their clinical efficacy compared to the best-available therapy. Studies have yet to emerge on the aztreonam-avibactam combination. Conclusions: Eravacycline and cefiderocol present promising results, offering similar or superior results to the already available antibiotic options. They create new possibilities for treating patients with highly resistant Gram-negative microorganisms. More studies are required to draw definite conclusions. Nonetheless, the new molecules offer hope for an otherwise grim future.