Abstract: To address the challenges of machining micro-deep holes with high aspect ratios and stringent morphological accuracy for pressure measurement orifices in cryogenic wind tunnel models made of 18Ni(200D) alloy, this study employs a Box-Behnken design to systematically investigate the effects of femtosecond laser parameters—single-pulse energy (100-160 μJ), scanning speed (100-800 mm/s), and repetition frequency (10-100 kHz)—on through-hole quality. Predictive models for the diameter deviation (η), average wall taper angle (α), and outlet ellipticity (ε) were established using Box-Cox transformation and second-order regression analysis. Residual diagnostics confirmed that the models satisfy the assumptions of normality, homoscedasticity, and independence. The results indicate that η is significantly influenced by the linear and quadratic effects of energy and scanning speed; α is primarily governed by the quadratic effects of scanning speed and repetition frequency; and ε exhibits highly significant linear and quadratic dependencies on all three factors. Response surface optimization revealed that optimal machining quality (η<3%,α≈9°,ε≈1.2) is achieved at approximately 130 μJ, 450 mm/s, and 50 kHz. This study defines an engineering-viable process window via the response surface methodology, enabling high-precision and repeatable micro-hole drilling on high-strength 18Ni(200D) alloy, thereby providing critical guidance for the precision manufacturing of pressure measurement orifices for cryogenic wind tunnel models.