Targeted therapies persist as the conventional method of treatment of kidney clear cell carcinoma (KIRC). However, resistance to these drugs emerges as a significant impediment to the management of renal cancer. MICAL-L2 plays a pivotal role in cytoskeleton rearrangement. This study sought to elucidate the clinical relevance of MICAL-L2 in KIRC and its regulatory mechanism driving cancer progression and resistance to therapy. TCGA data mining was utilized to assess the expression of MICAL-L2 in samples from patients with KIRC. Kaplan-Meier analysis and immunohistochemistry were employed to explore the clinical significance of MICAL-L2. In vitro experiments, including assays for wound healing and Transwell migration, CCK-8, EDU staining, RT-PCR, flow cytometry, and co-immunoprecipitation analysis were conducted to investigate the effects of MICAL-L2 on the drug sensitivity of KIRC cells and to elucidate the molecular mechanisms involved. The results showed that MICAL-L2 was overexpressed in KIRC tissues. High levels of MICAL-L2 were associated with poor survival and a poor response to drug therapy among patients with KIRC. Overexpression of MICAL-L2 stimulated cell migration, proliferation, and rendered KIRC cells insensitive to sunitinib and everolimus, two traditional therapies for KIRC. Furthermore, MICAL-L2 overexpression accelerated cancer progression and resistance to therapy in KIRC cells by interacting with its downstream regulator α-actinin-4 (ACTN4) in a Rab13-dependent manner, which reduced the degradation of ACTN4, leading to increased Vimentin expression. All these findings indicate that MICAL-L2 plays a crucial role in the progression of KIRC and suggest that MICAL-L2 may serve as a potential therapeutic target for KIRC treatment.