Male lacrosse and female lacrosse have differences in history, rules, and equipment. There is current debate regarding the need for enhanced protective headwear in female lacrosse like that worn by male lacrosse players. To inform this discussion, 17 high school lacrosse players (6 female and 11 male) wore the Stanford Instrumented Mouthguard during 26 competitive games over the 2021 season. Time-windowing and video review were used to remove false-positive recordings and verify head acceleration events (HAEs). The HAE rate in high school female lacrosse (0.21 per athlete exposure and 0.24 per player hour) was approximately 35% lower than the HAE rate in high school male lacrosse (0.33 per athlete exposure and 0.36 per player hour). Previously collected kinematics data from the 2019 high school male and female lacrosse season were combined with the newly collected 2021 kinematics data, which were used to drive a finite element head model and simulate 42 HAEs. Peak linear acceleration (PLA), peak angular velocity (PAV), and 95th percentile maximum principal strain (MPS95) of brain tissue were compared between HAEs in high school female and male lacrosse. Median values for peak kinematics and MPS95 of HAEs in high school female lacrosse (PLA, 22.3 g; PAV, 10.4 rad/s; MPS95, 0.05) were lower than for high school male lacrosse (PLA, 24.2 g; PAV, 15.4 rad/s; MPS95, 0.07), but the differences were not statistically significant. Quantifying a lower HAE rate in high school female lacrosse compared to high school male lacrosse, but similar HAE magnitudes, provides insight into the debate regarding helmets in female lacrosse. However, due to the small sample size, additional video-verified data from instrumented mouthguards are required.