Non-small-cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers worldwide but has limited effective therapies. Uncovering the underlying pathological and molecular changes, as well as mechanisms, will improve the treatment. Dysregulated microRNAs (miRNAs) have been proven to play important roles in the initiation and progression of various cancers, including NSCLC. In this manuscript, we identified microRNA-135b (miR-135b) as a tumor-promoting miRNA in NSCLC. We found that miR-135b was significantly upregulated and that its upregulation was associated with poor prognosis in NSCLC patients. miR-135b was an independent prognostic factor in NSCLC. Overexpressing miR-135b significantly promoted the aggressiveness of NSCLC, as evidenced by enhanced cell proliferation, migration, invasion, anti-apoptosis, and angiogenesis in vitro and in vivo, and knockdown of miR-135b had the opposite effects. Mechanistically, our results reveal that miR-135b directly targets the 3'-untranslated region (UTR) of the deubiquitinase CYLD, thereby modulating ubiquitination and activation of NF-κB signaling. Moreover, we found that interleukin-6 (IL-6)/STAT3 could elevate miR-135b levels and that STAT3 directly bound the promoter of miR-135b; thus, these findings highlight a new positive feedback loop of the IL-6/STAT3/miR-135b/NF-κB signaling in NSCLC and suggest that miR-135b could be a potential therapeutic target for NSCLC.