Colorectal cancer, one of the most fatal cancer types, has an unmet need for the development of targeted oral therapeutics. To address this, we propose to engineer a multiparticulate system to enhance the efficacy of anticancer drugs for treatment of colon cancer. We have developed a dual ligand- and pH-responsive multiparticulate system for oral drug delivery to the colon. Indomethacin (IND) and quercetin (QCT) preformulated as nanosuspensions (NSps) or liquid crystalline nanoparticles (LCNPs), respectively, were co-encapsulated into pH-responsive CA/HEC-MBs microbeads via ionoptropic gelation. To enhance tumor targeting, both nanoparticles were further coated with lactoferrin (Lf), which allows binding with Lf receptors on cancerous HCT-116 cells, resulting in higher internalization and superior cytotoxicity. Among various simulated gastrointestinal fluids, the engineered CA/HEC-MBs incorporating nanoparticles successfully released the drugs only in the colon (pH 6.8). Oral administration of both LF-targeted nanostructured microbeads into DMH-induced colorectal cancer bearing mice revealed superior in vivo anti-tumor efficacy. The microbeads efficiently reduced CEA and PCNA protein levels as well as the serum levels of IL-6, IL-1, and TNF-α. Apoptosis was also upregulated, as evidenced by increased Bax/Bcl2 ratio and increased expression levels of activated caspase-3 and caspase-9. Overall, these findings suggest that orally administered LF-targeted nanoparticle-based MBs for co-delivery of QCT and IND represent a promising alternative to conventional colon cancer therapy.