In a report it argues the "hardest to help" jobseekers remain at risk of being "parked". It adds they are given "little or no support" by providers who assess them as being unlikely to find sustained work.
The Work Programme is aimed at getting people who have been unemployed for more than a year into a job. It is delivered by 18 prime contractors and these providers are paid by results.
However, MPs said none of the 18 major providers met their targets in the first year of the programme. As they are paid on a payment-by-results system, the Government has spent about £248 million less on the Work Programme than anticipated in 2012/13, according to the report.
"The performance of the Work Programme in its first 14 months was poor," said Anne Begg, chair of the Work and Pensions Committee.
"There are signs it is now improving significantly for mainstream jobseekers. We hope the next job outcome statistics to be published in June will bear this out - we will be very concerned if they don't.
"However, the Work Programme has proved much less successful to date in addressing the problems faced by jobseekers who face more serious obstacles to finding a job - people with disabilities, homeless people, and those with a history of drug or alcohol abuse."
The Committee also highlights people with the severest barriers to work, such as homelessness and serious drug and alcohol problems, are often not ready for the Work Programme and need support first to prepare for it.
It recommends the Department for Work and Pensions (DWP) pilots ways of providing this additional support to prepare these groups for the Work Programme before they are referred.
Begg said: "At a time of low growth and high unemployment it is important that disadvantaged jobseekers are kept as close to the labour market as possible.
"The Government should be using the unspent Work Programme budget to fund a range of measures designed to tackle the long-term unemployment problem."
Following the publication of the report, the TUC has urged the Government not to ignore the failings of the Work Programme. Its general secretary, Frances O'Grady, said these findings "cannot be swept under the carpet".
"Providers of job support have failed to achieve their minimum performance targets and are not doing enough to help disadvantaged job seekers," O'Grady said.
"The committee is right to be 'dismayed' at the huge caseloads advisers are being landed with. This is clearly preventing them from providing the tailored assistance individuals need to find lasting employment."
She added: "Instead of continuing to fund failing programmes, the Government should introduce a job guarantee for all those facing long-term unemployment."
The DWP has said the programme was "clearly improving" as it has now helped more than 207,000 people into work.
"The payment-by-results model goes further than any previous scheme to encourage providers to help all claimants, including the hardest to help," a department spokesman said.
"The key point is they earn the majority of their payment for helping someone into work and keeping them there."