Papain is a proteolytic enzyme known for its exfoliating properties, capable of lysing dead skin cells on the skin’s surface. This study aimed to formulate and optimize a scrub cream containing dried crude papain as an active exfoliant. A 2² factorial design was employed, with stearic acid (10%)–triethanolamine (3%–4%) and cetyl alcohol (2%–2.5%) as formulation variables. The scrub cream was evaluated for its physical and chemical characteristics, including viscosity, flowability, spreadability, cream type, pH, and proteolytic activity. Proteolytic release was assessed using a Franz diffusion cell. The resulting formulations exhibited viscosities ranging from 60,000 to 102,000 cP at 2 rpm, spreadability between 76.74 and 116.12 g•cm/sec, and pH values from 7.64 to 7.95. Proteolytic activity ranged from 1.02 to 4.24 TU/mg. Stearic acid–triethanolamine significantly influenced spreadability, proteolytic activity, and pH, while cetyl alcohol affected all measured parameters. The optimized formulation consisted of stearic acid–triethanolamine (10%; 4%) and cetyl alcohol (2%). The release mechanism of papain from the scrub cream was identified as a combination of Fickian diffusion and matrix relaxation. These findings support the potential of dried crude papain as a viable active ingredient in exfoliating scrub cream formulations.