Low-grade serous ovarian carcinoma (LGSOC) is a rare ovarian cancer with high mortality rates. Recent clinical trials have shown that MEK inhibitors (MEKi) and CDK4/6 inhibitors (CDK4/6i) could provide therapeutic benefit to some patients. We previously examined MAPK pathway modulation due to MEKi treatment, but little is known about cell cycle pathway modulation using CDK4/6i in LGSOC. Therefore, we sought to investigate the expression of key cell cycle regulatory proteins in preclinical models of LGSOC, and to determine their sensitivities to CDK4/6i alone and in combination with MEKi. Protein expression of various cell cycle markers was measured by IHC and/or western blot in 144 LGSOC tumors and 10 patient-derived LGSOC cell lines.­­ Single and combined CDK4/6i (palbociclib) and MEKi (trametinib) treatments were evaluated. Efficacy was assessed by cell counting, drug synergy/growth inhibition calculations, and confirmed in a LGSOC cell-derived xenograft model. Loss of p16 was detected in 18% of primary and 42% recurrent tumors. Most cell lines lacked p16 expression, with low-moderate sensitivity to single palbociclib (PLB) treatment. As expected, KRAS/NF1-mutant cell lines had higher levels of MAPK pathway activation and higher sensitivity to single trametinib treatment. Contrary, KRAS/NF1-wt cell lines displayed higher pRb1 levels and were more responsive to dual treatment in-vitro and in-vivo. Furthermore, acquired resistance to trametinib resulted in increased resistance to PLB, and vice versa. In these cell lines, early detection of changes in cyclin E1 or pMAPK levels were associated with acquired drug resistance. Dual PLB and trametinib treatment could elicit synergistic cell inhibitory effects; however, their synergistic growth inhibition was limited to KRAS/NF1-wt LGSOC models. In the context of the ongoing clinical trials that are evaluating these inhibitors in recurrent LGSOC patients, these findings warrant closer investigation.