Drill string buckling behavior is of interest to the oil and gas industries. Buckling severity increases as drilling continues and causes a lockup condition beyond which drilling cannot commence. Friction force between the drill string and wellbore is key in influencing drill string buckling initiation and progression. Herein, the effects of adding nano-sepiolite (NSP) as an additive to water-based drilling fluids, on the friction between the drill string and wellbore wall were investigated. Various samples with different sizes and compositions of NSP were tested for their ability to reduce the coefficient of friction (COF) that delays the onset of buckling to facilitate deep drilling by providing improved lubrication characteristics. The drill string sinusoidal and helical buckling and lock-up condition and the axial force transfer (AFT) were experimentally investigated. The water-based drilling fluids lubricity, COF between the drill string and the wellbore wall, and the stability of the rheological properties of the NSP-modified water-based drilling fluids containing 1–6 wt.% NSP was tested in a high temperature and high pressure (HTHP) environment utilizing an in-house experimental setup. Sepiolite in nano-form at 4 wt. % and with a size distribution of 30–60 nm improved the stability of the water-based drilling fluids rheology and significantly decreased the COF of the water-based drilling fluids and improved the drill string axial force transfer. NSP additives significantly improved the COF and the drill string AFT in HTHP environment compared with that of other commercial drilling fluids.