ABSTRACT To evaluate the safety and efficacy of echinocandins (rezafungin, RZF; anidulafungin, AFG) in Candida albicans (C. albicans ) endophthalmitis, with a particular focus on the novel drug RZF. In vitro safety was assessed by CCK-8 and live/dead staining on ARPE-19, Müller, and RAW 264.7. For in vivo safety, we administered therapeutic doses via intravitreal injection in rabbit eyes and performed fundus photography and histopathological analysis on day 3. Antifungal effect evaluation included minimum inhibitory concentration (MIC) determination, biofilm inhibition, and structural damage observation (confocal laser scanning microscopy, CLSM; scanning/transmission electron microscopy, SEM/TEM). We measured inflammatory responses via TNF-α/IL-1β qRT-PCR in RAW 264.7 cells. A rabbit C. albicans endophthalmitis model was established. At 48 h post-infection, rabbits received intravitreal injections of liposomal amphotericin B (L-AmB, 10 μg), voriconazole (VCZ, 50 μg), RZF (35 μg), AFG (35 μg), or saline (control). Clinical scores, ocular fungal burden, aqueous humor TNF-α, and histopathological scores were assessed. Echinocandins showed lower IC50 values in vitro , yet maintained acceptable safety at clinically relevant low concentrations compared with traditional drugs, with no significant tissue toxicity in vivo . RZF and AFG exhibited lower MICs (0.016–0.03125 μg/mL) than L-AmB (4 μg/mL) and VCZ (0.125–0.25 μg/mL). All four drugs inhibited biofilm formation, disrupted fungal structures, and downregulated inflammatory responses. In vivo , RZF/AFG reduced clinical and histopathological scores, fungal burden, and TNF-α levels, performing similarly to traditional drugs. RZF and AFG demonstrate potent antifungal activity against C. albicans comparable to conventional drugs, along with significant anti-inflammatory effects and acceptable safety profiles.