Ibuprofen is a poorly soluble and poorly compressible drug and is unsuitable for “direct tableting”. Microcrystalline cellulose (Avicel® PH 101) based ibuprofen powder formulations have been comilled in presence of Aerosil® (colloidal silicon dioxide) as lubricant, and the total compression behavior was evaluated using the Cooper–Eaton equation. Scanning electron microscopy (SEM) revealed about the damage of crystal geometry of the crystalline drug after comilling. Differential scanning calorimetry (DSC) indicated decrease of melting endotherm (partially) attributing to the decrease in crystalline intensity of ibuprofen upon comilling. Small changes in the infrared spectra such as shift of characteristic bands, reduction in intensity, and appearance of new bands are mainly related to the possible physical interaction and/or amorphization of the drug in the comilled mixtures. Increased compaction can be achieved after milling of the microcrystalline cellulose based blends. Milling decreased particle size and improved wettability of the drug and increased dissolution. Microcrystalline cellulose based comilled ibuprofen powder with improved compression and dissolution may be taken as a future scope of scale up for “direct tableting”.