Jennie Golding, a co-author of the report from the Institute of Education at UCL, believes issues around confidence and a sense of belonging could be possible reasons why girls' performance has suffered.
But she said more research was needed to understand and address it, with boys and girls getting similar TIMSS scores in previous studies.
Mary Richardson, the report's other co-author, said: "It is possible that some of the effects of Covid, learning loss and changes to learning environments are now revealing themselves."
This is the first time the assessment has been fully digital, which may have had an impact on scores, researchers said.
A gender gap has opened up in favour of boys since the last report in comparative countries too, such as Australia, New Zealand and the United States.
In England, the gap is much closer when looking at Year 6 Sats results for 2024, where girls continued to outperform boys at the expected standard in all subjects apart from maths, where boys outperformed girls by one percentage point.
It is a similar story for older age groups doing their GCSEs and A-levels, where boys tend to outperform girls in maths and science but to a lesser degree than in the latest TIMSS study.
Part of the TIMSS study also found that more boys reported feeling "very confident" in maths than girls.
Tanya Tracey, chief executive of the charity Girls Are Investors, said many of the girls and young women they support have a fear of failure and lack confidence.
