Leprosy, tuberculosis and extreme violence led to the collapse of the Indus civilisation around 4,000 years ago.
Skeletal remains discovered in the ancient city of Harappa have shown how the city rose and fell rapidly between 2200-1900 BC, then largely vanished.
Compared to other ancient civilisations, little is known about the Indus civilisation, despite spanning over a million square miles and existing for over 1,000 years.
Published in the journal PLOS ONE, researchers at the Appalachian State University in North Carolina examined the skeletons at three Indus burial areas for evidence of trauma and infectious diseases.
Their results showed stark differences from the long-standing belief that they were peaceful, cooperative and egalitarian society without social hierarchies or differences in access to basic resources.
Lead author Gwen Robbins Schug said: "The collapse of the Indus Civilization and the reorganisation of its human population has been controversial for a long time.
"Early research had proposed that ecological factors were the cause of the demise, but there wasn't much paleo-environmental evidence to confirm those theories. In the past few decades, there have been refinements to the available techniques for reconstructing paleo-environments and burgeoning interest in this field."
Findings from their research showed socially disadvantaged communities in Harappa faced much bigger impacts from climate changes and socio-economic changes, particularly communities vulnerable to violence and disease.
"Rapid climate change events have wide-ranging impacts on human communities," Robbins Schug said. "Scientists cannot make assumptions that climate changes will always equate to violence and disease.
"However, in this case, it appears that the rapid urbanisation process in Indus cities, and the increasingly large amount of culture contact, brought new challenges to the human population. Infectious diseases such as leprosy and tuberculosis were probably transmitted across an interaction sphere that spanned Middle and South Asia."
Leprosy significantly increased through the Indus civilisation, with tuberculosis appearing later in its history.
Findings also showed that violent injuries also increased over time, which Robbins Schug says is remarkable given current evidence suggesting violence was rare in prehistoric South Asian areas.
"As the environment changed, the exchange network became increasingly incoherent. When you combine that with social changes and this particular cultural context, it all worked together to create a situation that became untenable."
They found that poorer members of society, who were excluded from the city's main cemeteries, faced the most violence. Half of the skulls examined showed evidence of violence, with 20% showing signs of leprosy.
"The evidence from Harappa offers insights into how social and biological challenges impacted past societies facing rapid population growth, climate change and environmental degradation. Unfortunately, in this case, increasing levels of violence and disease accompanied massive levels of migration and resource stress and disproportionate impacts were felt by the most vulnerable members of society."