Hepatocellular carcinoma (HCC) is a malignancy worldwide with one of the worst prognoses. Emerging studies have revealed that long noncoding RNAs (lncRNAs) contribute to HCC progression. This research probes the expression and regulatory effect of lncRNA SATB2-AS1 on HCC development. Reverse transcription-polymerase chain reaction (RT-PCR) was applied to measure the SATB2-AS1 profile in HCC tissues and adjacent non-tumor tissues. The impact of SATB2-AS1, miR-3678-3p, or GRIM-19 on HCC cell proliferation, growth, migration, invasion, and apoptosis was determined by gain- and loss-of-function experiments. The results revealed that SATB2-AS1 was downregulated in HCC tissues, and its lower levels were related to higher tumor staging and poorer prognosis of HCC patients. SATB2-AS1 overexpression repressed HCC cell proliferation, induced G1 arrest, and apoptosis, and inhibited migration, invasion, and epithelial-mesenchymal transition (EMT). Mechanistically, SATB2-AS1 inactivated STAT3/HIF-1α and strengthened GRIM-19 expression. After knocking down GRIM-19 with small interfering RNA (siRNA), the malignant phenotypes of HCC cells were enhanced. Further bioinformatics analysis showed that miR-3678-3p was targeted by SATB2-AS1. The dual-luciferase reporter assay, RNA immunoprecipitation (RIP) experiment, and Fluorescence in situ Hybridization (FISH) test confirmed that SATB2-AS1 sponged miR-3678-3p and the latter targeted GRIM-19. The rescue experiments showed that miR-3678-3p aggravated the malignant behaviors of HCC cells, whereas SATB2-AS1 overexpression reversed miR-3678-3p-mediated effects. Inhibition STAT3 promoted SATB2-AS1 and GRIM-19 expression, and reduced miR-3678-3p level. Activation STAT3 exerted opposite effects. Overall, this study confirmed that SATB2-AS1 is a potential prognostic biomarker for HCC and regulates HCC devolvement by regulating the miR-3678-3p/GRIM-19/STAT3/HIF-1α pathway.