Archaeological sites hold important clues to complex climate-human relationships of the past. Human settlements in the peripheral zone of Indus culture (Gujarat, western India) are of considerable importance in the assessment of past monsoon-human-subsistence-culture relationships and their survival thresholds against climatic stress exerted by abrupt changes. During the mature phase of Harappan culture between ~4,600–3,900yrsBP, the ~4,100±100yrsBP time slice is widely recognized as one of the major, abrupt arid-events imprinted innumerous well-dated palaeo records. However, the veracity of this dry event has not been established from any archaeological site representing the Indus (Harappan) culture, and issues concerning timing, changes in subsistence pattern, and the likely causes of eventual abandonment (collapse) continue to be debated. Here we show a significant change in crop-pattern (from barley-wheat based agriculture to ‘drought-resistant’ millet-based crops) at ~4,200 yrs BP, based on abundant macrobotanical remains and C isotopes of soil organic matter (δ¹³C_SOM) in an archaeological site at Khirsara, in the Gujarat state of western India. The crop-change appears to be intentional and was likely used as an adaptation measure in response to deteriorated monsoonal conditions. The ceramic and architectural remains of the site indicate that habitation survived and continued after the ~4,200yrsBP dry climatic phase, but with declined economic prosperity. Switching to millet-based crops initially helped inhabitants to avoid immediate collapse due to climatic stresses, but continued aridity and altered cropping pattern led to a decline in prosperity levels of inhabitants and eventual abandonment of the site at the end of the mature Harappan phase.