Suicide attempts by self-poisoning have become a critical health problem. This study aimed to investigate the trend, incidence, and the associated risk factors of suicide attempts by self-poisoning. A total of 7398 Egyptian patients were analyzed. The trend of suicide attempts by self-poisoning was analyzed using 6745 patients over four registry years from January 1, 2016, to January 1, 2020. Then, the associated risk factors behind attempted suicide by self-poisoning from January 1, 2019, to January 1, 2020, were assessed using 2523 suicide attempters by self-poisoning, 201 fatalities by self-poisoning, and another 653 survivors of accidental poisoning. Results showed a rising trend of suicide attempts by self-poisoning over the studied years. The incidence of suicide attempts through deliberate self-poisoning represented 26.63/1,000 (CI95%: 25.63-27.86) to the admitted patients and 26.10/100,000 (CI95%: 25.10-27.14) to the regional population. The death rate due to suicide attempts by self-poisoning was 2.08/100,000 (1.90-2.49). The case fatality rate and the proportionate mortality rate for suicide by self-poisoning were 7.38% (CI95%: 6.45-8.42) and 14.11% (CI95%: 12.4-16.0) respectively. Multivariate analysis revealed that attempted suicide by self-poisoning was predicted among patients aged <25 or 25-40 years old (OR = 27.49, CI95%: 15.28-49.64 and OR = 59.42, CI95%: 32.76-107.77 respectively), those of low or moderate socioeconomic status (OR = 35.03, CI95%: 21.32-57.56 and OR = 14.11, CI95%: 10.86-18.43 respectively), students (OR = 2.91, CI95%: 1.57-5.43) and those living in rural residency (OR = 4.12, CI95%: 3.27-5.19). Suicide attempts by self-poisoning exhibited an incremental rise across time which raises a serious concern. Efforts should be directed to overcome the mentioned risk factors triggering suicide attempts by self-poisoning.