The emergence of antifungal resistance in Candida species has led to a requirement to develop new drug delivery mechanisms to improve their treatment effectiveness. This paper discusses how lipid-polymer hybrid nanocarriers (LPHNs) can be used to deliver amphotericin B to the target. The formulation was prepared and consisted of biodegradable polymers in combination with phospholipid layers to enhance the efficiency of encapsulation of the drugs and uptake by the cells. Zeta potential, systematic characterization of particle size, and encapsulation efficiency were determined and showed the best stability and steady release patterns. In vitro antifungal susceptibilities revealed that LPHNs had much better activities than free drug formulations against the resistant Candida albicans strains. The increase of intracellular accumulation as evidence of the cellular uptake was confirmed by the studies that revealed the use of the hybrid nanostructure that enabled the contact with the membrane. Moreover, cytotoxicity studies also showed that the toxicity to mammalian cells was decreased, which shows better therapeutic safety. The results emphasize the possibility of LPHNs as a high level drug delivery system to be used in the treatment of antifungal drugs with better targeting and minimal adverse side effects. The future research ought to be conducted on the validation and clinical translation of this prospective nanocarrier system in vivo.