Background: In the modern era of therapeutics, the proniosomal system has been identified as the most intriguing one among various novel systems, thus considerably enhancing the bioavailability of low-soluble drugs. The current study aimed to study the enhancement of therapeutic efficacy of topotecan (TPT) with curcumin (CUR) coadministration. Materials and Methods: We optimized the preparation of niosomes, concerning concentrations of lecithin, span 60, and cholesterol. Seventeen trials were proposed by the selected design. All these batches were initially evaluated only for entrapment efficacy (EE), vesicle size (VS), and percentage of TPT release by the end of 12 h. Analysis of variance and generated regression equations were assisted to study the significant variables and magnitude of impact. Results: The desirability of 0.893 was achieved with the optimum concentrations of selected independent variables in attaining the highest EE (90.393%), minimum VS (386.264 nm), and percentage of TPT release (98.614% at 12 h). TPT and CUR release from the optimized formulation were found to be anomalous or non-Fickian diffusion, as evident from the n value of Peppas model. The cytotoxic studies demonstrated that TPT and CUR in liposomal and free forms were found to be less cytotoxic on MCF-7 model cells. All these findings indicate that the coadministration of CUR with TPT proniosomes can be a promising strategy to enhance the antitumor treatment.