Fluoroquinolones (FQs), a class of broad-spectrum antibacterial drugs, have recently garnered significant interest as potential anticancer treatment options. This review highlights the updated landscape of FQs in oncology, emphasizing the most recent synthesized FQ derivatives with enhanced anticancer potency and selectivity, covering articles published in 2024 and 2025. Through mechanisms such as topoisomerase I/II inhibition, cell cycle arrest, apoptosis induction, and the enhancement of RNA interference via TRBP binding, a variety of FQ-based scaffolds have shown substantial antiproliferative activity against a wide panel of cancer cell lines. Strategic alterations at positions C-1, C-3, C-6, C-7, and C-8 of the FQ core have a major impact on cytotoxic capability and target selectivity, according to structure–activity relationship (SAR) studies. FQ12 was the most effective of the reviewed FQ derivatives, especially against ovarian cancer cells. It also demonstrated synergistic effects with cisplatin against cisplatin-resistant A2780 cells, with negligible damage to normal cells. These results encourage more preclinical research on FQs and efforts to repurpose drugs, supporting their promise as a promising scaffold for the development of targeted, multi-mechanistic anticancer drug candidates.