Background: The changing lifestyles and dietary patterns in recent years have led to an increased incidence rate of colorectal cancer, posing a significant threat to the well-being and safety of patients. Therefore, the objective of this study was to investigate the therapeutic efficacy of the combination treatment of Aspirin and curcumin in a colorectal cancer model. The aim is to provide insights into potential approaches for managing this disease. Methods: All mice were randomly assigned to different groups, including sham, dextran sulphate sodium (DSS) + azoxymethane (AOM), Aspirin, Curcumin, and Union group, with six mice in each group. In vitro experiments utilized the human colon adenocarcinoma cell lines (HCT-116) as a model. For HCT-116 cells, TAp63alpha (TAp63α), si-TAp63α, negative control, or si-negative were transfected using Lipofectamine 2000, with three replicates per group. Quantitative polymerase chain reaction (qPCR) was performed to assess the expression levels of Lrg5 and TAp63α after treatment with Aspirin combined with curcumin, both in vivo and in vitro. The Cell Counting Kit-8 (CCK8) assay and 5-ethynyl-2-deoxyuridine (EDU) staining were used to evaluate the proliferation of colorectal cancer cells following combination treatment. Results: The combination treatment of Aspirin and curcumin resulted in a significant reduction in tumor numbers and tumor size in the colorectal cancer mouse model (p < 0.05). Moreover, this combination treatment led to reduced mRNA expressions of interleukin-6 (IL-6), IL-17α, and Prostaglandin-Endoperoxide Synthase 2 (Ptgs2) in the tumor tissue of the mouse model (p < 0.05). In HCT-116 cells, the combination treatment of Aspirin and curcumin demonstrated inhibitory effects on cell proliferation and migration rates. It also reduced the rate of EDU-positive cells and increased Caspase-3/9 activity levels (p < 0.05). Additionally, this combination treatment resulted in decreased glucose consumption, lactate production, and adenosine triphosphate (ATP) quantity in HCT-116 cells (p < 0.05). Furthermore, it reduced extracellular acidification rate and increased oxygen consumption relative to basal levels (OCR, oxygen consumption rate) in HCT-116 cells (p < 0.05). The combination treatment of Aspirin and curcumin suppressed the mRNA expressions of TAp63α and Lgr5 in both the mouse model and in vitro models (p < 0.05). It also downregulated the protein expressions of TAp63α, Lgr5, and p-β-catenin in both models (p < 0.05). Notably, Aspirin had no effect on TAp63α ubiquitination, while curcumin promoted TAp63α ubiquitination in HCT-116 cells. Furthermore, compared to curcumin alone, the combination treatment of Aspirin and curcumin further enhanced TAp63α ubiquitination in HCT-116 cells (p < 0.05). The regulation of TAp63α played a crucial role in mediating the effects of Aspirin combined with curcumin on colorectal cancer cell growth and the progression of the Warburg effect. Conclusions: The combination treatment of Aspirin and curcumin effectively suppresses the proliferation and migration of colorectal cancer cells both in vitro and in vivo by targeting the Warburg effect. This modulation of the Warburg effect is mediated through the TAp63a/Lgr5 signaling pathway. These findings highlight the potential therapeutic value of Aspirin combined with curcumin for the treatment of colorectal cancer.