There are challenges to implementing high-speed direct compression tableting for poor flow, low-density cohesive powder. Thus, excipients with adequate flowability and bulk density are desired to facilitate this process. As a major novelty, the effect of nano-sized silica (Aerosil 200®) on the extent of flow and packing properties enhancement was evaluated. A 3² full-factorial design was applied to investigate the influence of silica load (X1; 0.5–5%) and mixing time (X2; 1–10 min) as independent variables on flow, bulk density and compaction properties of microcrystalline cellulose (MCC). Optimized MCC-silica blend was subsequently used in tableting of Albuterol Sulphate as a model low-dose drug. Regression analysis demonstrated significant (p ≤ 0.05) effect of X1 and X2 on tableting properties of MCC with pronounced effect of X1. Besides, nano-sized silica exhibited a significant improve in flowability, bulk density and compaction properties of MCC. However, at higher silica loading (over 2.75%) a reduction in flow and compaction was observed. The superior performance of MCC was achieved at silica load of (2.40%) and mixing time of (9.66 min). Moreover, the optimized blend could be directly compressed into tablets with excellent content uniformity, adequate mechanical strength, fast disintegration (63 ± 0.64 s) and dissolution (>90% after 5 min) that leads to rapid response. Ultimately, dry coating of poor flow-low density powder using nano-sized silica is a promising approach to improve the content uniformity of low-dose tablets prepared by high speed direct compression tableting.