ABSTRACT Objectives To theoretically evaluate the efficacy and safety of large‐spot (i.e., > 4 mm) picosecond laser treatment for pigmented lesions in Asian skin using a melanosome disruption threshold fluence (MDTF) model. Materials and Methods The MDTF model was applied to calculate the required fluence for melanosome disruption with 532, 730, 755, 785, and 1064 nm picosecond lasers. To assess potential complication risks, energy deposition in surrounding tissues was simulated. Additionally, a clinical case series was conducted using a 1064 nm picosecond laser with a large spot size to evaluate its feasibility for treating an ectopic Mongolian spot and a nevus of Ota. Results At 532 nm, spot size had minimal impact on the required fluence for epidermal melanosome disruption and on collateral energy deposition. For 730–1064 nm wavelengths, the optimal spot size depended on the lesion depth. When targeting epidermal melanosomes, smaller spot sizes confined energy deposition to superficial layers, reducing collateral exposure. In contrast, for dermal melanosomes, larger spot sizes reduced the required fluence by 39%–65% and lowered collateral energy deposition, while also decreasing variation in required fluence across lesion depths. In the clinical validation, both dermal cases showed good clearance without adverse events, supporting the feasibility of this approach. However, increasing the energy output of laser devices may be necessary to achieve sufficient efficacy. Conclusion The theoretical analysis shows that at 532 nm, both small and large spot sizes can be effective for treating epidermal lesions. In contrast, at near‐infrared wavelengths, smaller spot sizes are preferable for epidermal lesions, whereas larger spot sizes are advantageous for dermal lesions, potentially lowering the risk of complications while maintaining effective target disruption. These findings provide practical clinical guidance by clarifying wavelength‐ and spot‐size‐specific strategies according to target depth. Furthermore, the present results may help optimize treatment parameters and device specifications and inform future clinical studies using large‐spot picosecond laser systems.