Despite significant efforts for early detection and treatment, lung cancer is often diagnosed at an advanced stage, with the average 5-year survival rate being at <15%. There is a gap in current therapeutic approaches against Lung Cancer (LC) and many other cancer types, with an absence of drugs that directly target the cell cycle and the cell-cycle associated genes, such as Cyclin-Dependent Kinases (CDKs). Only three molecules capable of inducing cell-cycle arrest (Ribociclib, Palbociclib, Abemaciclib), that inhibit CDK activity, have recently successfully translated to patient treatment, but only for specific types of breast cancer treatment, and none for lung cancer treatment. Just last year, several clinical trials were undergoing using promising miRNAs (miRs). miRs, natural products that are present in all cells, have emerged as important regulators of gene activity. We identified and studied two miRs, miR-143 and miR-506, which are consistently downregulated in LC samples and regulate the cell cycle progression. These miRs can induce G1/S and G2/M arrest of the cell cycle, inhibit proliferation, induce apoptosis, and downregulate the expression of three of the most crucial cell cycle CDKs, CDK4/6 and CDK1. More importantly, the combinatorial miR treatment had minimal apoptotic activity to normal cells and did not affect the expression of crucial for normal cell function CDKs (i.e., CDK 7/9). The objective of this study is to decipher the mechanistic behavior and evaluate the therapeutic potential of miR-143 and miR-506 in vivo against LC.