Cotton ginning facilities generate substantial quantities of airborne particulate matter during mechanical seed–fiber separation, fiber cleaning, and seed processing operations. Prolonged occupational exposure to cotton dust fractions — particularly PM10 and PM2.5 — is associated with byssinosis, chronic obstructive pulmonary disease, and other respiratory disorders. This study investigates the dust generation characteristics of a large-scale ginning plant operating in the Fergana Valley, Uzbekistan, and evaluates the performance of an integrated multi-stage air purification system comprising cyclone separators, fabric bag filters, and a wet scrubber unit. Dust concentration measurements were conducted at twelve sampling stations across primary processing, seed cleaning, and dispatch zones using real-time optical particle counters and gravimetric filter methods in accordance with ISO 7708 and NIOSH 0600 protocols. Results demonstrate that the optimized purification cascade reduced total suspended particle (TSP) concentrations from a pre-treatment mean of 78.4 mg/m³ to a post-treatment mean of 1.7 mg/m³, achieving an overall collection efficiency of 97.8%. Fabric filters exhibited the highest fractional efficiency for sub-5 μm particles (98.6%), while cyclone units effectively removed coarse lint (>50 μm) at efficiencies exceeding 92%. Computational fluid dynamics (CFD) simulations corroborated empirical data and identified inlet velocity optimization as a critical factor governing cyclone pressure drop and collection efficiency trade-offs. The findings provide evidence-based guidelines for retrofit design, regulatory compliance, and worker health protection in cotton processing industries across Central Asia.