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Fungal PJI is one of the most feared complications after arthroplasty. Although a rare finding, its high associated morbidity and mortality makes it an important object of study. The most frequent species causing fungal PJI is <i>C. albicans</i>. New technology to treat this type of PJI involves organic–inorganic sol-gels loaded with antifungals, as proposed in this study, in which anidulafungin is associated with organophosphates. This study aimed to evaluate the efficacy of an anidulafungin-loaded organic–inorganic sol-gel in preventing prosthetic joint infection (PJI), caused by <i>Candida albicans</i> using an in vivo murine model that evaluates many different variables. Fifty percent (3/6) of mice in the <i>C. albicans</i>-infected, non-coated, chemical-polished (CP)-implant group had positive culture and 100% of the animals in the <i>C. albicans</i>-infected, anidulafungin-loaded, sol-gel coated (CP + A)-implant group had a negative culture (0/6) (<i>p</i> = 0.023). Taking the microbiology and pathology results into account, 54.5% (6/11) of <i>C. albicans</i>-infected CP-implant mice were diagnosed with a PJI, whilst only 9.1% (1/11) of <i>C. albicans</i>-infected CP + A-implant mice were PJI-positive (<i>p</i> = 0.011). No differences were observed between the bone mineral content and bone mineral density of noninfected CP and noninfected CP + A (<i>p</i> = 0.835, and <i>p</i> = 0.181, respectively). No histological or histochemical differences were found in the tissue area occupied by the implant among CP and CP + A. Only 2 of the 6 behavioural variables evaluated exhibited changes during the study: limping and piloerection. In conclusion, the anidulafungin-loaded sol-gel coating showed an excellent antifungal response in vivo and can prevent PJI due to <i>C. albicans</i> in this experimental model.