Background <p>Colorectal cancer (CRC) is one of the most common malignancies of the gastrointestinal tract and remains a leading cause of cancer-related mortality. Hypoxia and pyroptosis are closely linked to malignant progression and may shape tumour biology and the immune microenvironment.</p> Methods <p>Pyroptosis- and hypoxia-related genes were obtained from GeneCards and MSigDB, and PHRGs were defined as the intersection of pyroptosis- and hypoxia-associated gene sets for subsequent consensus clustering. Transcriptomic profiles and survival information for CRC were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Pyroptosis- and hypoxia-related molecular subtypes were identified using consensus clustering. Least absolute shrinkage and selection operator and Cox regression analyses were applied to construct a prognostic signature. Key signature genes were preliminarily assessed at the expression level in paired CRC and adjacent normal tissues using qRT-PCR (<i>n</i> = 10 pairs) and western blotting (<i>n</i> = 6 pairs). Given the limited sample size and lack of stage- or subtype-stratified validation, these experiments provide preliminary expression-level support rather than functional confirmation.</p> Results <p>Patients were classified into four PHRG-related molecular subtypes with distinct prognoses and biological characteristics, with PHRGcluster C2 showing the worst outcome. A total of 1578 pyroptosis- and hypoxia-related differentially expressed genes (PHRDEGs) were identified across the four PHRGclusters. A six-gene prognostic signature (PHRDEGscore) was then established in the TCGA cohort. Patients with a high PHRDEGscore had shorter survival, which was validated in external cohorts (GSE39582 and GSE17536). The low-PHRDEGscore group exhibited higher immune infiltration (e.g., activated CD8+ and CD4+ T cells), and an exploratory association with immunotherapy response was observed in a non-CRC immunotherapy-treated cohort (IMvigor210). Experimental analyses indicated higher mRNA levels of HES4, SHROOM2, and OXCT1 in CRC tissues than in adjacent normal tissues (qRT-PCR, <i>n</i> = 10 pairs), and increased protein expression of HES4 and SHROOM2 (western blotting, <i>n</i> = 6 pairs).</p> Conclusions <p>This study identified hypoxia- and pyroptosis-related molecular patterns and a six-gene prognostic signature in CRC. The observed associations are correlative and hypothesis-generating. Prospective validation in independent, well-annotated clinical cohorts is needed before any clinical application can be considered.</p>