Despite advancements in breast cancer (BrCa) treatments, dose-limiting toxicities caused by off-target exposure to healthy tissues remain a significant barrier to effective treatment options. This study aimed to enhance the anticancer properties of paclitaxel (PTX) and honokiol (HNK) through encapsulation in planetary-ball milled nanoparticles (PBM-NP) and coating with MUC1-aptamer (S2.2) for targeted delivery. Both in silico and in vitro methods were used to evaluate the efficacy of the encapsulation of PTX and HNK in aptamer-conjugated PBM-NPs (PTX-S2.2-PBM NP and HNK-S2.2-PBM NP). Pharmacokinetic simulations demonstrated the potential advantage of using PTX and HNK in combination while targeting MUC1 for BrCa treatment. Tissue microarray analysis confirmed the expression of MUC1 in BrCa tissues. It was found that MUC1 tissue expression was stage-dependent, with the highest MUC1 expression observed in Stage IV BrCa tissue (93.9%) compared to Stage III (36.5%), Stage II (11.3%), and Stage I (0.4%), respectively. NHS coupling was utilized to synthesize PTX-S2.2 and HNK-S2.2 PBM-NPs. Dynamic light scattering (DLS), FTIR, and HPLC were utilized to characterize the NPs. Cytotoxicity was assessed using MTT and Live/Dead cell assays. DLS analysis revealed that the NPs have a desirable size and zeta potential that are suitable for systemic circulation and improved therapeutic outcomes. Successful encapsulation and conjugation were confirmed through FTIR and HPLC analysis. Cell viability and proliferation studies demonstrated that PTX-S2.2-PBM NPs and HNK-S2.2-PBM NPs, when used individually, exhibited cytotoxicity comparable to or greater than that of free PTX and HNK, respectively. When combined, a synergistic effect was observed. Utilizing copolymers (PCL/PEG) and aptamer conjugation, PTX has the potential for improved bioavailability and reduced off-target effects compared to its free drug counterparts. Based on these findings, we believe that PTX-S2.2 and HNK-S2.2 PBM NP could represent a promising treatment option for BrCa.