The Mental Health (MH) of college students is increasingly becoming a public health concern, with rising rates of depression, anxiety, and stress. This study aims to explore the relationship between Biomechanical Factors (BF), Physical Activity (PA), and MH outcomes in college students, addressing gaps in current research that frequently overlook the biomechanical features of physical well-being. A cross-sectional observational design was employed, involving 200 college students aged 18–24. SP underwent comprehensive assessments, including postural analysis, movement pattern evaluation, and MH screening. Physical activity levels and cognitive resilience were also measured to evaluate their roles in mediating and moderating the relationships between BF and MH. Key findings revealed that poor biomechanical alignment, such as forward head posture and movement asymmetry, were significantly associated with higher levels of depression, anxiety, and stress. Correlation analysis showed that forward head posture correlated positively with depression (r = 0.52, p < 0.01) and anxiety (r = 0.47, p < 0.01). Movement asymmetry was also associated with MH disturbances (depression: r = 0.45, p < 0.01). PA mediated the relationship between BF and MH, with significant indirect effects via PA for forward head posture (0.18, p < 0.05). Cognitive resilience emerged as a significant moderator, buffering the negative impact of biomechanical inefficiencies on MH outcomes. Within-subject comparisons indicated improvements in BF and MH scores over a one-month follow-up, with decreases in forward head posture (−2.2 ± 1.5 degrees, p < 0.05) and depression scores (−1.5 ± 1.2, p < 0.01).