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Simple Summary: The incidence of colorectal cancer (CRC) is dramatically increasing. There is a great need to better understand the mechanisms and factors involved in the development and progression of CRC, as well as to assess their diagnostic and prognostic significance. Deactivation of tumor suppressor genes that regulate many cell processes, such as the cell cycle and apoptosis, is often observed in cancer pathogenesis; therefore, the purpose of our study was to analyze the expression level of the SAV1 gene, which encodes one of the main components of the Hippo suppressor pathway, and to estimate its prognostic significance in CRC. We showed that SAV1 mRNA and protein levels in tumor tissues differed significantly from those observed in non-cancerous mucosa, and we were the first to provide evidence that reduced SAV1 protein expression is associated with unfavorable clinicopathological parameters in CRC patients and appears to be involved in the development and progression of CRC. Salvador homolog-1 (SAV1) is a component of the Hippo pathway that regulates tissue growth and homeostasis by affecting diverse cell processes, including apoptosis, cell division, and differentiation. The aberrant expression of Hippo pathway components has been observed in various human cancers. This study aimed to examine the expression level of the SAV1 gene in colorectal cancer (CRC) and its prognostic value and associations with tumor progression. We obtained matched pairs of tumor tissue and non-cancerous mucosa of the large intestine from 94 CRC patients as well as 40 colon biopsies of healthy subjects collected during screening colonoscopy. The tissue samples and CRC cell lines were quantified for SAV1 mRNA levels using the quantitative polymerase chain reaction method, while SAV1 protein expression was estimated in the paired tissues of CRC patients using immunohistochemistry. The average level of SAV1 mRNA was decreased in 93.6% of the tumor tissues compared to the corresponding non-cancerous tissues and biopsies of healthy colon mucosa. A downregulated expression of SAV1 mRNA was also noted in the CRC cell lines. Although the average SAV1 immunoreactivity was increased in the CRC samples compared to the non-cancerous tissues, a decreased immunoreactivity of the SAV1 protein in the tumor specimens was associated with lymph node involvement and higher TNM disease stage and histological grade. The results of our study suggest that the impaired expression of SAV1 is involved in CRC progression. [ABSTRACT FROM AUTHOR]