Irrational use of antibiotics in livestock and poultry farming and food processing leads to antibiotic residues, making the development of efficient and rapid detection methods particularly important. In recent years, up-conversion nanoparticles (UCNPs) have attracted considerable attention for antibiotic detection in foods due to their large anti-Stokes shift, low autofluorescence, and high photostability. Focusing on optical sensors constructed with functionalized UCNPs, this article summarizes the luminescence mechanisms, design and synthesis strategies, surface functionalization methods, and main sensing mechanisms of UCNPs. It reviews recent progress on UCNP-based optical sensors for the detection of various antibiotics, including tetracyclines, quinolones, and β-lactams, and analyzes the characteristics and applicability of different sensing strategies. Furthermore, this review discusses the current challenges in material preparation and applicability to complex food matrices, as well as the future application prospects of UCNP-based optical sensors in on-site rapid detection and portable detection platforms.