Methotrexate-encapsulated solid lipid nanoparticles (MTX-SLNs) and lactoferrin-decorated MTX-loaded nanoparticles (MTX-Lf-SLNs) present a promising strategy for treating colorectal cancer. Among different molecular targets, MTX demonstrated the highest affinity for Caspase-6, exhibiting a docking score of -9.316, while molecular dynamics validated stable interactions. The optimized nanoparticles displayed a spherical shape (~ 160 nm, as observed in TEM images) with a high drug encapsulation efficiency of 85.87% for MTX-SLNs and 80.11% for MTX-Lf-SLNs, which ensured improved stability. Structural analyses using FTIR, DSC confirmed effective drug encapsulation and the binding of lactoferrin. Interestingly, MTX-Lf-SLNs demonstrated higher cytotoxicity (IC50: 0.51 µM) compared to MTX-SLNs and free MTX, inducing apoptosis and stopping cell cycle progression in HCT116 cells. This improved effect was associated with receptor-driven absorption through lactoferrin targeting. Nanoparticulate formulations decreased TNF-α (17.6 ± 2.1 pg/mL), IL-6 (20.2 ± 1.9 pg/mL), and IL-1β (15.4 ± 3.4 pg/mL), thereby reducing immune activation. The nanoparticles exhibited extended, pH-sensitive drug release (70% at pH 5.7) and significant anti-angiogenic effects (~ 70% inhibition in CAM assay). Moreover, they enhanced the balance of reactive oxygen species and safeguarded mitochondria, thereby lowering overall toxicity. Migration assays further validated their capacity to obstruct cancer cell invasiveness, suggesting a potential to impede metastasis. Utilizing the bioactivity of lactoferrin for precise delivery, MTX-Lf-SLNs offer an attractive approach to enhance anti colon cancer efficacy while reducing unwanted side effects.