The quality of teaching, leadership and management in science is among the worst of all secondary subjects, says Estyn.
It wants to focus on curriculum, assessment and standards, particularly among 14 to 19-year-olds where achievement is generally lower than in the primary years.
The review will include an assessment of new science GCSEs, introduced in September to offer teachers and pupils different approaches to the subject.
A spokesman said: "The quality of teaching, leadership and management in science are among the lowest of all secondary subjects. These factors go some way towards explaining the low science standards."
Susan Lewis, chief inspector of schools in Wales, has raised concerns about science in her annual reports. In 2003-4 it was included among the weakest subjects at KS3. Last year's report showed that half of all inspected KS4 science lessons received grade 3 on a scale of one to five - a higher proportion than any other subject.
Estyn recognises that heads of science often face extra problems because of the complexity and size of their departments and difficulty recruiting the right staff.
UK-wide research by the Department for Education and Skills and the National Foundation for Educational Research in 2004 found that just 19 per cent of physics teachers and 25 per cent of chemistry teachers had the relevant qualifications, compared with 44 per cent of biology teachers.
Estyn wants training to enhance the abilities of non-specialist teachers but insists standards will only improve with stronger leadership and management.
The agency added: "Useful and innovative teaching resources and materials are available, but these are only as effective as the extent to which teachers buy into them.
"For these improvements to become embedded successfully, heads of departments must establish and maintain an effective learning culture."
However Liz Pollock, head of science at Penglais school in Aberystwyth, disagreed with Estyn's assessment.
She said: "Ceredigion has very good science results, so maybe we're not typical.
"I've got good experienced teachers and young enthusiastic ones, and when we recruit we don't have a problem.
"We've got a good management structure within the department, so I've got people in charge of KS3 and 4 and people in charge of biology, chemistry and physics, so we share the jobs out.
"It really comes down to strong leadership from the head."
Estyn said it welcomed last month's call by the Assembly government's enterprise, innovation and networks committee for the agency to work with others to tackle staffing issues and make the subject more attractive to students.